B., Sayyed, S. G., Lichtnekert, J., Tikoo, K., and Anders, H. J. J. Physiol. The role of molecular regulation and targeting in regulating calcium/calmodulin stimulated protein kinases. [1][2] To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space, the endoplasmic reticulum (ER), and sometimes into the mitochondria. 98, 730742. Mol. It is intimately related to events triggering increased inflammatory processes, such as oxidative stress and secretion of neurohormones (Di Lullo et al., 2017). This can cause a spontaneous release of neurotransmitters via sympathetic or parasympathetic nerve channels. In summary, TG mice led to a worsening of the arrhythmogenic profile of the mice in addition to increasing their risk of life. In addition to CNB1 and RCN1 that are known to play a role in the calcium signalling pathway, the protein kinase gene CMK2, the sphingolipid homeostasis-related gene ORM2 and the gene SIF2 encoding the WD40 repeat-containing subunit of Set3C histone deacetylase complex are involved in the calcium sensitivity of yeast cells to miR-34c-5p and CaMKII are involved in aldosterone-induced fibrosis in kidney collecting duct cells. Calciumcalmodulin (CaM)-dependent protein kinase II (CaMKII) is the most abundant protein in excitatory synapses and is central to synaptic plasticity, learning and doi: 10.1371/journal.pone.0130477, Clapham, D. E. (2007). Moreover, activation of CaMKII in macrophages is initiated by a significant trigger elevation of intracellular Ca2+. J. Clin. doi: 10.1002/path.4489, Backs, J., Backs, T., Neef, S., Kreusser, M. M., Lehmann, L. H., Patrick, D. M., et al. 5:21. doi: 10.3389/fphar.2014.00021, Picciotto, M. R., Zoli, M., Bertuzzi, G., and Nairn, A. C. (1995). Type 1 and 2 CRS are considered cardiorenal and are characterized by a loss of cardiac function leading to renal injury (Damman et al., 2007). Its inhibition has been constantly suggested as treatment for these pathologies (Rokita and Anderson, 2012; Cipolletta et al., 2015). Calcium/calmodulin-dependent protein kinases (CaMKs) are key regulators of calcium signaling in health and disease. Adv. Dial. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II. It is important to note that acute type 5 CRS can overlap a chronic injury (Ronco and Di Lullo, 2014). doi: 10.1016/j.molimm.2012.04.008, Brown, J. H., Del Re, D. P., and Sussman, M. A. Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II. doi: 10.1007/s10047-011-0613-5, Hoeker, G. S., Hanafy, M. A., Oster, R. A., Bers, D. M., and Pogwizd, S. M. (2016). [2] These include muscle contraction, neuronal transmission (as in an excitatory synapse), cellular motility (including the movement of flagella and cilia), fertilization, cell growth (proliferation), neurogenesis, learning and memory as with synaptic plasticity, and secretion of saliva. doi: 10.1016/j.yjmcc.2011.07.016, Sakagami, H., Kamata, A., Nishimura, H., Kasahara, J., Owada, Y., Takeuchi, Y., et al. Besides the activation via Ca2+/CaM that is dependent on several Ca2+ factors, such as the total Ca2+ available in a dose-dependent manner and its spark frequency, amplitude, and duration, the CaMKII can be activated via post-translational modifications as, for example, by reactive oxygen species (ROS) (Beckendorf et al., 2018). Studies show this kinases function, suggesting that CaMKK translocates to the nucleus under stimulation, and the inhibition of translocation directly implies the deactivation of monocytic cells (Guest et al., 2008). Among the CaMKs, the most abundant in the heart is CaMKII (Luczak and Anderson, 2014). IUBMB Life 51, 215221. (A) Autoinhibition of each 12 CaMKII monomers; (B) Activation of CaMK monomers by Ca2+/CaM complex (direct activation) or by post-translational modifications as by ROS (autonomous activation). doi: 10.1152/ajprenal.00358.2017, Pellicena, P., and Schulman, H. (2014). Finally, CRS type 5 is a systemic disorder that reaches both organs simultaneously. Oncogene 34, 48084820. Cell. During HF independent of renal injury, we can note the expression of transcription factors, angiogenic factors, and natriuretic factors, often used as biomarkers of this condition. 73, 112116. Soc. A. Ca2+ current facilitation is CaMKII-dependent and has arrhythmogenic consequences. [23][24] Once the Ca2+ is released from the ER the egg starts the process of forming a fused pronucleus and the restart of the mitotic cell cycle. This region is composed of approximately 20 amino acids, positively charged and containing hydrophobic residues (Islam, 2020). In conclusion, more studies are necessary to further understand the role of CaMKII in CRS. 202, 753755. Hyperphosphorylation caused by CaMKII of this site leads to an increase of spontaneous elementary Ca2+-release events from the sarcoplasmic reticulum especially during diastole (Mustroph et al., 2017). Longev. Sci. Ca2+/CaM-stimulated protein kinase kinase (CaMKK), CAMKK1 and CAMKK2, produce CaMKK and CaMKK, respectively. Calcium signaling. Oxidative stress injury in doxorubicin-induced cardiotoxicity. The severe cardiorenal syndrome: Guyton revisited. This stress may be maintaining the previously mentioned cycle of damage. doi: 10.1016/j.yjmcc.2014.02.004, Maier, L. S., and Bers, D. M. (2007). CaMKII inhibitors: from research tools to therapeutic agents. On some models, the KN-93 does not seem to prevent but to slow the arrhythmia (as longer cycle length) without marked alterations in baseline ECG characteristics (Hoeker et al., 2016). Toxicol. It is the most used one in studies that require the blocking of CaMKII, and it is resistant even to proteolysis. Curr. 37, 251265. (2019). Med. (2020). Liu, L., Li, Y., and Tollefsbol, T. O. Renal failure increases cardiac histone H3 acetylation, dimethylation, and phosphorylation and the induction of cardiomyopathy-related genes in type 2 diabetes. (2018). Calcium is a ubiquitous second messenger with wide-ranging physiological roles. PLoS One 10:e0139350. It uses statistical analysis to predefine gene sets involved in a specific cellular process. WebCalmodulin (CaM) is a ubiquitously expressed 16.7 kDa Ca 2+ binding protein best known for its ability to activate CaM-dependent kinases in a variety of cells. Fail. Evolutionary aspects of calmodulin. Mol. In general, while the heart is responsible for providing nutrients and oxygen-rich fluids to the body through blood flow, the kidney is responsible for providing electrolytes, acid-base homeostasis, vitamin D activation, and erythropoietin synthesis (Ronco and Di Lullo, 2014). doi: 10.1016/j.toxlet.2019.02.013, Sumi, M., Kiuchi, K., Ishikawa, T., Ishii, A., Hagiwara, M., Nagatsu, T., et al. Site-specific methionine oxidation in calmodulin affects structural integrity and interaction with Ca2+/calmodulin-dependent protein kinase II. Natl. A. P. (2020). In the kidneys, CaMKII expression is associated to aldosterone-induced fibrosis (Park et al., 2018; Zhang et al., 2018) and also shows that the increase in mitochondrial fragmentation observed in hyperglycemia stress-mediated renal damage is due to the JNK-CaMKII-Fis1 pathway (Zhang et al., 2018). doi: 10.1161/01.ATV.17.9.1746, Ke, H. Y., Chin, L. H., Tsai, C. S., Lin, F. Z., Chen, Y. H., Chang, Y. L., et al. Alarcon, M. M. L., Trentin-Sonoda, M., Panico, K., Schleier, Y., Duque, T., Moreno-Loaiza, O., et al. Cell. Science 293, 11031105. 1131, 16. (2014). miR-200a-5p augments cardiomyocyte hypertrophy induced by glucose metabolism disorder via the regulation of selenoproteins. 291, 2084920857. In types 3 and 4, for example, renal failure increases cardiac histone H3 epigenetics, evidencing the crosstalk between renal failure and the transcription of cardiomyopathy-related genes (Gaikwad et al., 2010). Res. doi: 10.1007/978-3-030-12457-1_26, Skelding, K. A., Rostas, J. Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Signaling occurs when the cell is stimulated to release Ca2+ ions from intracellular stores, and/or when Ca2+ enters the cell through plasma membrane ion channels. (2017). In addition to the redox balance, other factors indirectly contribute to cardiac and renal alterations. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. The most known are KN-93 and AC3-I. PLoS One 3:e1606. All authors contributed to the article and approved the submitted version. Although Ca (2+)/CaM is required for proliferation in both unicellular and multicellular eukaryotes, the Yet there are few studies involving both organs in a systemic profile. Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins by Ca (2+). doi: 10.1126/science.293.5532.1103, Yamauchi, T. (2005). Once depolarized the sarcoplasmic reticulum (SR) releases Ca2+ into the myoplasm where it will bind to a number of calcium sensitive buffers. Exp. [19], Astrocytes have a direct relationship with neurons through them releasing gliotransmitters. Determining whether the CRS is a type 1 or 2 represents a challenge for clinicians since the majority of diagnostics are made when both organs are already injured. doi: 10.1093/ndt/gfu026, Bers, D. M., and Morotti, S. (2014). Chem. No use, distribution or reproduction is permitted which does not comply with these terms. Ca2+ may also result from internal stores found in the SR. Calcium (Ca 2+) is a universal second messenger involved in various cellular processes, leading to plant development and to biotic and abiotic stress responses. Physiological and unappreciated roles of CaMKII in the heart. Although Orai1 and STIM1, have been linked by several studies, for a proposed model of store-operated calcium influx. Med. It was first mentioned as a Ca2+-dependent regulator (Kakiuchi and Yamazaki, 1970). (2019). doi: 10.1371/journal.pone.0001606, Hanada, S., Takewa, Y., Mizuno, T., Tsukiya, T., Taenaka, Y., and Tatsumi, E. (2012). Figure 2. This release may be caused by Ryaodine (RYRs) or IP3 receptors. This mechanism occurs after CaMKII selectively phosphorylates HDAC4. doi: 10.1016/j.jacc.2017.05.035, Mustroph, J., Neef, S., and Maier, L. S. (2017). Marsico, F., Paolillo, S., Gargiulo, P., Parisi, V., Nappi, C., Assante, R., et al. Cell. (2012). These Ca2+ signals integrate extracellular and intracellular fluxes, and have been implicated to play roles in synaptic plasticity, memory, neurotransmitter release, neuronal excitability, and long term changes at the gene transcription level. CaMKII could be crucial to the progression of CRS, more specifically related to the progression from acute HF to chronic (types 1 and 2). Transplant. Together with this, the present study aims to focus on CaMKII relevance and how it is implied specifically during cardiorenal syndrome (CRS). Catalytic activity is required for calcium/calmodulin-dependent protein kinase IV to enter the nucleus. 29, 18211827. Front. U.S.A. 106, 23422347. While Ca2+ is associated with inflammation, studies have shown a connection between oxidative stress and CaMKII activation (Erickson et al., 2008). Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Heart failure: advanced development in genetics and epigenetics. Besides, CKDs significantly affects the regulation of cardiac Ca2+ by mechanisms not yet clarified (Ke et al., 2020). 114, 13771388. Med. 14, 29. WebThis review considers each pathway of the three different isoforms of calmodulin (CaM1; CaM2; CaM3) and focuses on some common proteins involved in the three pathways, doi: 10.2353/ajpath.2010.090528, Guest, C. B., Deszo, E. L., Hartman, M. E., York, J. M., Kelley, K. W., and Freund, G. G. (2008). Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats. Cardiol. doi: 10.3892/mmr.2019.9817, Rajtik, T., Carnicka, S., Szobi, A., Giricz, Z., O-Uchi, J., Hassova, V., et al. doi: 10.1016/j.cell.2007.11.028, Colombo, P. C., Ganda, A., Lin, J., Onat, D., Harxhi, A., Iyasere, J. E., et al. Cell Calcium 82:102063. doi: 10.1016/j.ceca.2019.102063, Kakiuchi, S., and Yamazaki, R. (1970). In other words, it is a CaM-competitive CaMKII inhibitor. Camk2n1 is a negative regulator of blood pressure, left ventricular mass, insulin sensitivity, and promotes adiposity. This is 20,000- to 100,000-fold lower than typical extracellular concentration. Calmodulin - Definition, Function and Structure | Biology 141, 808818. Many factors have been suggested to contribute to these conditions, for instance, sepsis, infections, drugs, toxins, and diabetes. Oxid. Nat. doi: 10.1111/jcmm.13740, Zhang, Y., Feng, J., Wang, Q., Zhao, S., Yang, S., Tian, L., et al. Nat. doi: 10.1021/bi027097h, Mnzel, T., Camici, G. G., Maack, C., Bonetti, N. R., Fuster, V., and Kovacic, J. C. (2017). doi: 10.4161/cc.10.4.14798, Snijder, J., Rose, R. J., Raijmakers, R., and Heck, A. J. R. (2011). CaM) is a dumbbell shaped protein ubiquitously present in eukaryotes that mediates calcium-dependent signalling.CaM can bind four calcium ions (Ca 2+) in its N- and C-lobes (two ions per lobe) and thereby regulate numerous Ca 2+-dependent pathways [13].Both N- and doi: 10.1038/nrg2521, Montgomery, H. J., Bartlett, R., Perdicakis, B., Jervis, E., Squier, T. C., and Guillemette, J. G. (2003). This prevents cross species fertilization to occur. Another study shows the high capacity to inhibit the binding of CaM with NaV1.5, increasing the calcium release from RYR2 in cardiomyocytes independent from CamKII (Johnson et al., 2019). *Correspondence: Marcela Sorelli Carneiro-Ramos, marcela.ramos@ufabc.edu.br; msorelli@gmail.com, These authors have contributed equally to this work, Kidney and Distant Organ Crosstalk in Health and Disease, View all Cell. Circ. (2014). Lett. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. CaMKIV is observed in the regulation of cyclic AMP, plasticity, fear memory, inflammatory sensibility, and control of the cell cycle (Skelding and Rostas, 2020). (2005). Biochem. Ther. CaMKIV only encodes one gene, CAMK4, coding the monomerics isofroms: and (Skelding and Rostas, 2020). Type 3 CRS is defined as acute nephron-cardiac syndrome, occurring when acute renal failure leads to the development of acute cardiac injury. Lack of some of these components means sensitization to antifungal drugs. Central Physiol. Studies have pointed out the role of epigenetics in the development of CRS (Gaikwad et al., 2010). (2015a). Am. doi: 10.1016/j.ejphar.2018.12.011, Kassler, P., Bauersachs, J., Busse, R., and Schini-Kerth, V. B. The CaMKI family constitutes four elements, each of them encoding a different gene: CAMK1 (CaMKI), PNCK (CaMKI/Pnck), CAMK1G (CaMKI/CLICK3), and CAMK1D (CaMKI/CKLiK), which are found in higher quantity in mice brains (Picciotto et al., 1995). Circ. 234, 40954103. These families do not share common domains or structures, making them more specific to certain stimuli and pathways. doi: 10.1016/j.cardfail.2007.04.008, Di Lullo, L., Bellasi, A., Barbera, V., Russo, D., Russo, L., Di Iorio, B., et al. Front. Calcium (Ca 2+) is an essential signaling molecule that controls a wide range of biological functions. However, it is unclear if Ca 2+ /CaM signalling interferes with Here, the rise of intracellular calcium (Ca 2+) in cardiomyocytes Liu, M., Lang, N., Chen, X., Tang, Q., Liu, S., Huang, J., et al. doi: 10.1159/000495681, Zhang, Y., Zhang, M., Xu, W., Chen, J., and Zhou, X. They are responsible for many functions (Skelding and Rostas, 2020). Additionally, we have observed that CaM/CaMKII has been extensively studied in cardiovascular diseases; however, there is still the necessity of exploring how CaM could integrate Ca2+ signal in different scenarios, such as CRS. miR-185 Plays an Anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways. Intracellular variation in free Ca 2+ concentration is among the earliest events following the plant perception of environmental change. 18, 450458. The isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. (2006). In this paper, we review multiple calcium signaling pathways, including the IP3 (inositol 1,4,5-trisphosphate)-Ca 2+ (calcium ion) pathway, the p38-MAPK (mitogen-activated protein kinase) pathway, and the calmodulin binding pathway, which are involved in biological clock, intestinal microbial activity, and nerve excitability to regulate The CaMKII inhibitor (CaMK2n) has been shown to protect cardiac dysfunction and ameliorate injuries observed in metabolic syndrome (Prasad et al., 2015). Ca can act in signal transduction resulting from activation of ion channels or as a second messenger caused Cell. When a Ca2+ influx occurs, cross bridges form between myosin and actin leading to the contraction of the muscle fibers. Under in vitro and in vivo stimulations with isoproterenol, arrhythmias have been abolished after using NK-93 (Sag et al., 2011). 131, 101111. Organs 15, 140145. Calciumcalmodulin (CaM)-dependent protein kinase II (CaMKII) is the most abundant protein in excitatory synapses and is central to synaptic plasticity, learning and memory. doi: 10.1093/ndt/14.suppl_2.2, Erickson, J. R., Ling, M., Joiner, A., Guan, X., Kutschke, W., Yang, J., et al. Invest. MiR-625-5p suppresses inflammatory responses by targeting AKT2 in human bronchial epithelial cells. J. Mol. Nat. (2018). doi: 10.1161/HYPERTENSIONAHA.118.12409, Anavekar, N. S., McMurray, J. J. V., Velazquez, E. J., Solomon, S. D., Kober, L., Rouleau, J. L., et al. One of the major pathways in which calcium is involved is excitation contraction coupling. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors. Toxicol. doi: 10.1126/scisignal.2005046, Johnson, C. N., Pattanayek, R., Potet, F., Rebbeck, R. T., Blackwell, D. J., Nikolaienko, R., et al. This is the main reason it is used more in the studies concerning the participation of CaMKII in many cell functions. Exp. MicroRNA-133 controls cardiac hypertrophy. Calmodulin kinases: essential regulators in health and disease. Cancer Lett. 740, 703730. WebTitin binding. J. They encode four distinct genes (Luczak and Anderson, 2014). The Rac and Rho Hall of Fame. Acta Cir. Physiol. Since the origin of eukaryotes, the amino acids that compound CaM have not changed at all (Friedberg and Rhoads, 2001). The literature suggests that the Ca2+/CaM complex might be an important modulator of inflammation and oxidative stress via CaMKII in the kidneyheart interaction (summarized in Figure 2), and CaMKII regulation by pre- or post-translational mechanisms is essential for cardiac or renal homeostasis. Exp. Cardiac arrhythmias after renal I/R depend on IL-1. Regulation of multifunctional calcium/calmodulin stimulated protein kinases by molecular targeting. Am. Plenary lecture. [11] Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels,[12] activity of ion pumps, and components of the cytoskeleton.[13]. Biochem. Am. 13, 599608. Physiol. Biochem. doi: 10.1159/000493716, Keywords: CaMKII, cardiorenal syndrome, inflammation, immune system, cardiovascular diseases, Citation: Junho CVC, Caio-Silva W, Trentin-Sonoda M and Carneiro-Ramos MS (2020) An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome. (2008). Res. Reduced arrhythmia inducibility with calcium/calmodulin-dependent protein kinase II inhibition in heart failure rabbits. KN-93 also reduces diastolic cytosolic [Ca2+] after induced HF (Sag et al., 2011). Cell 131, 10471058. Physiol. 174, 187195. J. Nephrol. Nephrol. Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Cell. Cell. Biol. doi: 10.1182/blood-2008-03-144022, Liu, Z., Finet, J. E., Wolfram, J. doi: 10.1371/journal.pone.0139350, Virz, G. M., Clementi, A., De Cal, M., Brocca, A., Day, S., Pastori, S., et al. In addition to miRs, the role of long noncoding RNAs (lncRNAs) is well known. Acta 1840, 901905. WebIn all organisms in which the CaM gene has been deleted, it is essential. Additionally, inflammation leads to the release of renin, activating the renin-angiotensin-aldosterone system (RAAS), which activates the sympathetic nervous system (SNS) by increasing serum norepinephrine concentrations and is the cause of ROS release from the inflammatory cells (Bongartz et al., 2005). Studies have already shown that CaMKII is capable of modulating NF-B, IL-10, IL-2, and IL-4 production (Rusciano et al., 2019). 28, 13421354. Acad. CaMKII is a serine-threonine kinase, and it was first identified in the central nervous system, where it represents only 2% of the total protein. Biophys. (1999). Epigenetic modifications are highly coordinated processes of change that are not restricted to a specific phase of life. This pathway is mainly related to several cellular processes, including glucose homeostasis, hematopoietic stem cell maintenance, cell proliferation, apoptosis, and normal immune cell function (Skelding and Rostas, 2012). Pharmacol. J. Cardiol. Curr. doi: 10.1016/j.hrthm.2019.01.013, Lu, Y., Zhang, Y., Shan, H., Pan, Z., Li, X., and Li, B. Once hemodynamic parameters are restored, renal and cardiac homeostasis is also restored (Hanada et al., 2012). Methionine oxidation and reduction in proteins. doi: 10.1038/nature12537, Friedberg, F., and Rhoads, A. R. (2001). Rev. Allergy 2, 242256. Opin. 16 Articles, This article is part of the Research Topic, The Calcium-Calmodulin-CAMKII Signaling Axis Has a Crucial Role in Cardiac Function, The Role of CAMKII in Cardiorenal Syndrome, Oxidative Stress and Epigenetics Factors as CAMKII Regulators, http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm, Creative Commons Attribution License (CC BY). The main multifunctional families of kinases proteins are CaMKI, CaMKIV, CaMKK, and CaMKII (Hudmon and Schulman, 2002). CaMKII is the most abundant isoform in the heart; although classically described as a regulator of excitationcontraction coupling, recent studies show that it can also mediate inflammation in cardiovascular diseases (CVDs). Commun. Med. CRS type 1, known as acute, is described by acute cardiac injury leading a renal one through hemodynamic mechanisms (Di Lullo et al., 2017). Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA-1. Biochemistry 44, 94869496. 22, 26972707. Some examples of gliotransmitters are ATP and glutamate. 6:6779. doi: 10.1038/ncomms7779, Wang, K., Liu, F., Zhou, L. Y., Long, B., Yuan, S. M., Wang, Y., et al. Recent studies have cited the phospholipase A2 beta,[6] nicotinic acid adenine dinucleotide phosphate (NAADP),[7] and the protein STIM 1[8] as possible mediators of ICRAC. Physiol. Proc. Besides arrhythmias, CaMKII is strongly increased during myocardial injury (Ren et al., 2003), atrial fibrillation (Liu et al., 2019), cardiac hypertrophy (Kamada et al., 2019), ischemia/reperfusion injury (Rajtik et al., 2016), and heart failure (HF) (Beckendorf et al., 2018). doi: 10.1016/j.ijcard.2015.10.019, Zhang, R., Xu, Y., Niu, H., Tao, T., Ban, T., Zheng, L., et al. Circulation 128, 17481757. As mentioned above, one of the mechano-chemotransductions that ROS induces Ca2+ release by CaMKII involves NOS (Jian et al., 2014). In an inflammatory process as observed during CKD and chronic heart failure (CHF), cytokines are released by circulating and tissue-resident inflammatory cells (monocytes mainly) and play an important role in the progression of these diseases (Yogasundaram et al., 2019). Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome. J. Cardiovasc. On the other hand, the multifunctional kinases control many cell functions in different cell types, which makes them a powerful controller of other kinases. [20] Activation of these neurons will lead to an increase in the concentration of calcium in the cytosol from 100 nanomolar to 1 micromolar.[21]. (2015). Mol. Curr. doi: 10.1007/s00395-018-0688-8, Beckerman, P., Ko, Y. doi: 10.1016/j.canlet.2010.11.009, Liu, X., Yao, M., Li, N., Wang, C., Zheng, Y., and Cao, X. Calmodulin (Cal cium-modul ated protein, a.k.a. Invest. Contractions of skeletal muscle fiber are caused due to electrical stimulation. doi: 10.1161/CIRCULATIONAHA.111.067306, Wagner, S., Dybkova, N., Rasenack, E. C. L., Jacobshagen, C., Fabritz, L., Kirchhof, P., et al. Many of Ca2+ mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. (2012) suggest that inflammation during CRS is controlled by positive feedback mechanisms. (2019). As proposed by Beckendorf et al. Cardiorenal syndrome and heart failurechallenges and opportunities. Cardiovasc. It also prevents arrhythmias after models of acidosis, DOX-induced, NO-donor SNAP (Mustroph et al., 2017). Even though physiological levels of oxidative species are necessary for cellular function, the oxidative stress caused by the overproduction of these molecules in both organs leads to a series of structural abnormalities via immune system activation and fibrotic promotion (Virz et al., 2015a). Understanding how the kidney and heart relate has been a challenge since the Middle Ages, when Aetius of Amida initially attempted to explain fluid overlay by attributing it to kidney hardening (Diamandopoulos, 1999). Arrhythmogenic -adrenergic signaling in cardiac hypertrophy: the role of small-conductance calcium-activated potassium channels via activation of CaMKII. [25] Ca2+ release is also responsible for the activation of NAD+ kinase which leads to membrane biosynthesis, and the exocytosis of the oocytes cortical granules which leads to the formation of the hyaline layer allowing for the slow block to polyspermy. 69, 255265. 351, 12851295. 431, 14401459. Oncotarget 8, 4756547573. Neuronal Ca2+/Calmodulin-dependent protein kinase IIdiscovery, progress in a quarter of a century, and perspective: implication for learning and memory. Can. Eur. Med. Cell. doi: 10.18632/oncotarget.17735, Singh, M. V., Swaminathan, P. D., Luczak, E. D., Kutschke, W., Weiss, R. M., and Anderson, M. E. (2012). WebCalcium Signaling Pathway Molecular Basis of Cardiovascular Disease (Second Edition), 2004 Add to Mendeley Signal Transduction and Second Messengers Aldebaran M. Hofer, in Cell Physiology Source Book (Fourth Edition), 2012 Intracellular Signal Transduction Pathways 91 VA. Cyclic AMP Pathway 91 VB. doi: 10.1159/000438459, Voigt, N., Li, N., Wang, Q., Wang, W., Trafford, A. W., Abu-Taha, I., et al. Card. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Activation of constitutive nitric oxide synthases by oxidized calmodulin mutants. CRS, already cited, seems to be one of them. However, Alfazema and collaborators showed, recently, in a translational study, that deletion of CaMK2n1, diminishes CaMKII activity in the kidney and heart without affecting adipose tissue (Alfazema et al., 2019). Received: 16 March 2020; Accepted: 08 June 2020;Published: 14 July 2020. In relation to kidney disease, Park et al. B., Lee, M., Vlach, J., Novikov, N., Niedziela-Majka, A., et al. Inflammatory mechanisms in myocardial infarction. With the recent development of epigenetic studies, the use of ChIP-seq to evaluate H3 phosphorylation and binding of CaMKII across the genome enables a profound knowledge of the genome-wide functional effect of H3 alteration by CaMKII (Awad et al., 2015). CaMKII has been already described as fundamental for cardiac hypertrophy development (Cruz Junho et al., 2019). These include the mitogen-activated protein This miRNA targets pro-hypertrophic genes, such as RhoA, Cdc42, and Stim1 in the heart. Calmodulin (CaM) is an important calcium sensor protein that transduces Ca 2+ signals in plant stress signaling pathways. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. It is important to mention that epigenetics in CRS itself are little studied when compared to the traditional mechanisms even though it is very promising. doi: 10.1161/JAHA.115.001949, Puri, B. K. (2020). This is responsible for increases in vascular diameters. This kinase modulates numerous biological processes, such as the Ca2+ homoeostasis, excitement of membrane, cell cycle, cytoskeletal organization, and gene expression (Yamauchi, 2005; Backs et al., 2009). This type of release increases the activation of protein kinase, and is seen in cardiac muscle where it causes excitation-concentration coupling. The influx have been observed to occur via membrane Ca2+ conduits and Ca2+ stores in the sperm. Cell Biol. CaM was identified as a regulator of RyR2 single channels in lipid bilayers 1989 (16). This suggests that KN-93 has interactions with the CaM-Ca2+ binding; however, to inhibit CaMKII specifically, more affinized compound is necessary. Commun. The catalytic domain is blocked by the regulatory domain in an autoinhibitory way, keeping the enzyme inactive (Figure 1). J. Struct. Physiology and pathology of cardiac CaMKII. J. Med. This progresses to the activation of myeloid differentiation factor 88 (MyD88)- dependent and Toll/interleukin-1 receptor domain, prompting proinflammatory factors. 181, 968975. Transplant. These influxes are often spontaneous and localized as seen in the colon and portal vein, but may lead to a global Ca2+ wave as observed in many vascular tissues. (2016). WebPathways and Function Calmodulin is ubiquitously expressed in eukaryotic cells and acts as a general calcium sensor. (2018) shows that the oxidative stress in mitochondria can be reduced after the inhibition of CaMKII, alleviating the myocardial ischemia-reperfusion injury. The study of CRS is of great relevance for clinical treatment, considering that cardiovascular diseases represent the main cause of death in the United States for at least the last 15 years, according to the Centers for Disease Control and Prevention (CDC)1. One of them is the CaM that triggers conformational changes in response to Ca2+ oscillations (Carafoli and Krebs, 2016). They can be restricted to a small number of substrates (Islam, 2020) while the multifunctional kinases have wide specificity and regulate multiple functions in the same and different cell types (Skelding et al., 2011). There is a study from our group using interference RNA (RNAi) to block the expression of CaMKII. J. Nucl. In May 2023, Frontiers adopted a new reporting platform to be Counter 5 compliant, in line with industry standards. NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage. Inflammation also causes progressive renal dysfunction and fibrosis, which continues to injure the organ, maintaining the cycle. doi: 10.1038/nm1582, Carlstrom, M., and Montenegro, M. F. (2019). Kidney Int. This process is caused by the depolarization of the transverse tubular junctions. 4:e001949. J. Artif. This isoform of NOS produces an excessive amount of NO that mediates impaired vasoconstriction, which may be further worsened by the decreased of eNOS activity (Jian et al., 2014). Invest. 70, 212229. J. Neurochem. It is worth mentioning the role of miR-1, once alterations in its expression or inhibition have been discovered in many cardiac pathologies (Yang et al., 2007; Lu et al., 2009). WebCalcium (Ca(2+)) is an essential ligand that binds its primary intracellular receptor calmodulin (CaM) to trigger a variety of downstream processes and pathways. (2015). Physiol. Regarding inflammatory processes, miR-625-5p has been illustrated to inhibit inflammatory response in human bronchial epithelial cells and is downregulated in heart diseases once miR-625-5p is able to inhibit STAT3 and reduce the expression of CaMKII. (2017) demonstrated that the expression of long noncoding RNAs TINCR was downregulated in the heart after a transverse aortic constriction (TAC) model (Shao et al., 2017). 49, 20602072. (2018) shows that miR-34c-5p and CaMKII are involved in aldosterone-induced fibrosis in the kidneys. [14] Besides calmodulin, there are many other Ca2+-binding proteins that mediate the biological effects of Ca2+. Inhibition of CaMKII alleviates myocardial ischemia? J. Mol. Cardiorenal Med. The CaMKIV can translocate between the cytoplasm and nucleus. Calmodulin (CaM) is the main calcium sensor in all eukaryotes and can sense changes in the concentration of Ca 2+. Knockout of toll-like receptors 2 and 4 prevents renal ischemia-reperfusion-induced cardiac hypertrophy in mice. doi: 10.3969/J.ISSN.1673-4254.2018.02.10, Krol, J., Loedige, I., and Filipowicz, W. (2010). 11:735. doi: 10.3389/fphys.2020.00735. in response to haemodynamic cardiac stress. (2018). A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. (2015) show that miR-185 not only acts as the genes mentioned, but also targeting genes involved in Ca2+-associated pathological hypertrophy, including CamKII. WebThe calcium-calcineurin signaling pathway consists of various channels, transporters, pumps, and other proteins or enzymes. (1997). 116, 31273138. As mentioned, the AC3-I blocker, is a highly specific inhibitor of CaMKII. [22] It has also been seen that some model systems mix these methods such as seen with mammals. Med. CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages. It is coupled to a variety of other calcium-sensitive proteins It plays a fundamental role in every cell by amplification of the Ca2+ signal (Clapham, 2007). (2007). A., Wanner, C., Sarnak, M. J. I, Pia, L., McIntyre, C. W., Komenda, P., et al. Trentin-Sonoda, M., da Silva, R. C., Kmit, F. V., Abraho, M. V., Monnerat Cahli, G., Brasil, G. V., et al. The focus of studies is linked to inflammation and oxidative stress, which we know to be the consequences of CRS. 10, 2536. Oxidative stress triggers an inflammatory response, and this response induces more oxidative stress. Cardiol. One year later, in 1991, Sumi M and collaborators described a new and more selective inhibitor called KN-93 (Sumi et al., 1991). J. Physiol. A., and Joles, J. Res. The triggers to these Ca2+ influxes may differ. doi: 10.1111/jnc.14020, Thomas, B., Matsushita, K., Abate, K. H., Al-Aly, Z., rnlv, J., Asayama, K., et al. The pathological crosstalk between both organs is called cardiorenal syndrome (CRS), in which cardiac and renal dysfunction overlap; a disorder in one organ leads to acute or chronic dysfunction of the other organ (Ronco, 2011; Ronco and Di Lullo, 2014). Oxidative activation of CaMKII in acute myocardial ischemia/reperfusion injury: a role of angiotensin AT1 receptor-NOX2 signaling axis. doi: 10.1056/NEJMoa041365, Anbanandam, A., Bieber Urbauer, R. J., Bartlett, R. K., Smallwood, H. S., Squier, T. C., and Urbauer, J. L. (2005). 119, 19401951. CaMKII and are expressed mainly in the neural system while the CaMKII and isoforms are predominantly expressed in cardiac tissue (Backs et al., 2009). (2015). The second is a rapid time dependent change in the membrane potential which leads to a very quick and uniform increase of Ca2+. J. Med. Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. Adv. One of them is epigenetics factors. Recently, research has highlighted the involvement of CaMK2 in cancer development. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. The endothelial dysfunction caused by oxidative stress leads to uncoupling of endothelial NOS (eNOS), leading to the production of more ROS (Mnzel et al., 2017). 285, 218. (2019). In addition, recent studies have focused on MiR regulation and exosomes, specialized nanosized membranous vesicles, in different experimental models. In addition, Kim et al. In other words, when Ca2+ binds to CaM, it induces a structural modification, forming a Ca2+/CaM complex (Clapham, 2007). J. Intern. Cell Cycle 10, 631639. Calmodulin-dependent signalling pathways are activated and Dial. Cell. This has been observed in a number of smooth muscle tissues including arteries, portal vein, urinary bladder, ureter tissues, airway tissues, and gastrointestinal tissues. (2018). (2018), the Thr287 autophosphorylation causes what they denominate CaM trapping, increasing the CaM binding affinity to 1000-fold, maintaining the CaMKII activity even under low Ca2+ conditions (Beckendorf et al., 2018). 844, 110117. 1, 5258. Hypertension 74, 687696. The Ca2+ in the myoplasm will diffuse to Ca2+ regulator sites on the thin filaments. doi: 10.1016/j.cophys.2017.07.003, Carafoli, E., and Krebs, J. A study involving patients with CRS type 3 shows that they have an increased level of inflammatory and oxidative stress factors, including IL-6, myeloperoxidase, nitric oxide (NO), copper/zinc superoxide dismutase (SOD), and endogenous peroxidase (Virz et al., 2015a). Calmodulin (CaM) is a low-molecular-weight protein highly conserved in the eukaryotes (Clapham, 2007). Calcium signaling: from basic to bedside. Ca2+ is a versatile messenger molecule implied in many basic processes, such as contraction, potentiation, cell proliferation and apoptosis, and others (Carafoli and Krebs, 2016). Calmodulin regulation (calmodulation) of the family of voltage-gated Ca V 1-2 channels comprises a prominent prototype for ion channel regulation, remarkable for its Blood 112, 49614970. Slowly, epigenetics is gaining space, and traditional mechanisms (such as RAAS and inflammation) are being replaced by other patterns of findings and prevention. CaMKII-dependent SR Ca leak contributes to doxorubicin-induced impaired Ca handling in isolated cardiac myocytes. Sci. Genes, genetics, and epigenetics: a correspondence. doi: 10.1172/jci37059, Cipolletta, E., Rusciano, M. R., Maione, A. S., Santulli, G., Sorriento, D., Del Giudice, C., et al. Many inflammatory cytokines are enhanced in experimental models of renal ischemia (TNF-a, IL-1, and IL-6) and also markers, including the factor nuclear kappa B (NF-kB), which is very important for cell signaling during inflammatory processes (Trentin-Sonoda et al., 2015). 65:4315. (2013). New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin- dependent kinase II (CaMKII). doi: 10.1161/01.RES.0000216039.75913.9e, Bui, J. D., Calbo, S., Hayden-Martinez, K., Kane, L. P., Gardner, P., and Hedrick, S. M. (2000). The widespread regulation of microRNA biogenesis, function and decay. doi: 10.1016/j.jmb.2019.02.001, Wu, C. T., and Morris, J. R. (2001). 113, 112. Nowadays, it is well established that an adverse imbalance in hemodynamics caused by impaired kidney function can directly impact the heart (Anavekar et al., 2004). PLoS One 10:e0130477. 5:144. doi: 10.3389/fphar.2014.00144, Bongartz, L. G., Cramer, M. J., Doevendans, P. A., Bram, B. Biol. Biol. Cardiorenal syndrome: pathophysiology. Previous studies report that lncRNAs play critical roles in the modulation of heart development and cardiovascular diseases (Wang et al., 2014, 2015; Zhang et al., 2016, 2017). Calcium signaling is the use of calcium ions (Ca ) to communicate and drive intracellular processes often as a step in signal transduction. These may communicate both locally and globally in the cell. The mechanisms through which ICRAC occurs are currently still under investigation. (2015). These characteristics are fundamental to diseases acquired throughout life. Such an association with the plasma membrane creates the relatively new perception of the ER and theme of "a neuron within a neuron." Chem. doi: 10.1016/0006-291X(91)92031-E, Takemoto-Kimura, S., Suzuki, K., Horigane, S. I., Kamijo, S., Inoue, M., Sakamoto, M., et al. J. Restricted CaMK have three main families: phosphorylase kinase (PhK), elongation factor 2 kinase (eEF2K), and myosin light chain kinase (MLCK) (Skelding and Rostas, 2012). (2019). doi: 10.1016/j.pharmthera.2016.10.006, Navarro-Garca, J. Med. For that action, it involves some catalytic activity as catalytically inactive CaMKIV remains in the cytoplasm (Lemrow et al., 2004). Eur. CaMKII is observed in eukaryotes in four distinct isoforms (, , , ). During cardiac hypertrophy, there is an activation of fetal cardiac genes, an important mechanism regulated by CaMKII-mediated H3 chromatin regulation. Some proteins maintain a redox sensor that regulates the cell response to oxidative stress (Kim et al., 2014). In this review, we aimed to discuss the role of CaMK as an inflammatory mediator in heart and kidney interaction by conducting an extensive literature review using the database PubMed. CaMKII activity in the inflammatory response of cardiac diseases. Rep. 19, 19511957. Reperfusion injury by reducing mitochondrial oxidative stress in isolated perfused rat heart. J. Pathol. J. Biochem 51, 17781798. Cardiol. Chem. Biochem. doi: 10.1016/0006-291X(70)90199-3, Kamada, R., Yokoshiki, H., Mitsuyama, H., Watanabe, M., Mizukami, K., Tenma, T., et al. However, the specific effects of CaMK2 It is known that CaMKI translocates to the nucleus mediated by CRM1 complex after an influx of intracellular Ca2+ induced by potassium depolarization or glutamate (Sakagami et al., 2005). Regulation of Ca2+ dynamics is the most basal method to control the function of a kinase, mainly intracellular concentration of Ca2+ (Skelding and Rostas, 2012). J. Biol. A previous study has revealed that transgenic rice over-expressing the calmodulin gene OsCam11 (LOC_Os03g20370) is more tolerant to salt stress than wild type. This can lead to three different results. 1, 34. Control of histone H3 phosphorylation by CaMKII. Last but not least, among the CaMKs, we have the CaMKII. Calmodulin may activate the Ca2+-calmodulin-dependent protein kinases, or may act directly on other effector proteins. Biophys. It has also been seen that sperm binds to membrane receptors that lead to a release in Ca2+ from the ER. Pro-apoptotic effects of plasma from patients with cardiorenal syndrome on human tubular cells. In addition, studies have shown the role of NOS in the kidney, demonstrating that, when NOS activity is compromised, there are a series of renal dysfunctions that reduce glomerular perfusion and filtration, which may lead to a progressive scenario of hypertension and kidney injuries (Carlstrom and Montenegro, 2019). Hence, differently from other types of CRS, type 5 is relatively easier to identify the starting point of the CRS. STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer. Sci. Endocrinology 143, 36513657. JCI Insight 3:e120728. Global cardiovascular and renal outcomes of reduced GFR. Res. Therapeutic value of stimulating the nitrate-nitrite-nitric oxide pathway to attenuate oxidative stress and restore nitric oxide bioavailability in cardiorenal disease. Circulation 125, 20592070. J. (2015). Its function is further explained in the next section. nicotinic acid adenine dinucleotide phosphate, "The role of STIM and ORAI proteins in phagocytic immune cells", "Phospholipase C signaling and calcium influx", "Activation mechanism for CRAC current and store-operated Ca2+ entry: calcium influx factor and Ca2+-independent phospholipase A2beta-mediated pathway", "Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum", "Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation", "IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond", "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes", "Calcium indicators and calcium signalling in skeletal muscle fibres during excitation-contraction coupling", "Mitochondrial free Ca levels and their effects on energy metabolism in Drosophila motor nerve terminals", "Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume", "ScienceDirect.com | Science, health and medical journals, full text articles and books", https://en.wikipedia.org/w/index.php?title=Calcium_signaling&oldid=1154556380, Creative Commons Attribution-ShareAlike License 4.0, DAG attaches to the plasma membrane and recruits, This page was last edited on 13 May 2023, at 07:46. An important item to bring up is that KN-62/93 binds to the holoenzyme and directly steps in the interaction of Ca2+/CaM but does not directly bind to CaM (Sumi et al., 1991). RYRs Ca2+ release is spontaneous and localized. 314, F329F342. A., Anderson, M. E., Ai, X., and Donahue, J. K. (2019). In this scenario, the inhibition of CaMKII would be cardioprotective. Arterioscler. Immunochemical localization of calcium/calmodulin-dependent protein kinase I. Synapse 20, 7584. For example, miR-185 has a key role during cardiac hypertrophy. The cardiorenal syndrome: basis and common ground for a multidisciplinary patient-oriented therapy. 279, 1166411671. Pharmacol. Exp. Diseases associated with CAMK2A include Intellectual Developmental Disorder, Autosomal Recessive 63 and Intellectual Developmental Disorder, Autosomal Dominant 53.Among its related pathways are Calmodulin induced events and Signaling Biol. 84, 434441. During cardiac ischemia, myocytes release inflammatory cytokines (Colombo et al., 2012), and they can reach renal tissue, inducing local inflammation, apoptosis, or oxidative stress (Ronco and Di Lullo, 2014). Heart failure in chronic kidney disease: conclusions from a kidney disease: improving Global Outcomes (KDIGO) Controversies Conference. Epigenetics is the area of biology that studies changes in the functioning of a gene that is not caused by alterations in the DNA sequence and that perpetuate in the meiotic or mitotic cell divisions (Wu and Morris, 2001). Thus, GSA is especially useful to infer functions of different miRNAs. Approximately 7080% of patients with end-stage renal disease present type 4 CRS, presenting cardiac complications, such as infarct and long-term arrhythmias (Di Lullo et al., 2017). doi: 10.1016/j.cell.2008.02.048, Erickson, J. R., Pereira, L., Wang, L., Han, G., Ferguson, A., Dao, K., et al. CaM is one of these proteins, and this oxidation leads to a regulatory cascade response with specific targets, including CaMKII (Snijder et al., 2011), plasma membrane Ca2+ (Anbanandam et al., 2005), and nitric oxide synthase (NOS) (Montgomery et al., 2003). Am. A., Fernndez-Velasco, M., Delgado, C., Delgado, J. F., Kuro-o, M., Ruilope, L. M., et al. doi: 10.1152/ajpcell.00208.2016, Liu, H. J., and Liu, B. The close relation between inflammation and oxidative stress in pathophysiological processes also makes the balance between oxidant and antioxidant forces and, therefore, oxidative stress, one of the most important mechanisms as has been demonstrated in heart and kidney injury studies (Li et al., 2017; Oliveira et al., 2017; Liu and Liu, 2018; Songbo et al., 2019). Long non-coding RNAs: insights into functions. J. Cardiol. Pharmacol. 271, 56175622. Cardiol. Once bound to Ca 2+ /CaM, the multimeric CaMKII is released from its autoinhibitory status and maximally activated, which then leads to an intraholoenzyme autophosphorylation reaction. doi: 10.1172/jci.insight.120728, Zhang, M., Gu, H., Chen, J., and Zhou, X. Inflammation initiates vascular dysfunction, reducing the myocardial contractility and increasing myocardial cell death, linking CRS to apoptosis (Virz et al., 2015b). Bras. Each RyR2 subunit in a tetramer can bind one molecule of CaM. Med. Front. Pathological hypertrophy and compromised contractility are described to increase DNA methylation levels. doi: 10.1681/ASN.2016050562, Tokumitsu, H., and Soderling, T. R. (1996). doi: 10.1016/j.hfc.2013.12.003, Rusciano, M. R., Sommariva, E., Douin-Echinard, V., Ciccarelli, M., Poggio, P., and Maione, A. S. (2019). Eur. In pathological situations, increased diastolic Ca2+ in cytosol can activate the electrogenic NCX, which can cause delayed afterdepolarizations. The first is a uniform increase in the Ca2+ concentration throughout the cell. Oxidative stress in CaMKII by methionine-oxidized CaMKII was also observed in patients with atrial fibrillation (Purohit et al., 2013; Yoo et al., 2018), which also demonstrates that oxidative stress can act in part through increased constitutive activity of CaMKII, creating a highly vulnerable substrate within the HF that promotes atrial fibrillation beyond fibrosis. [15], Contractions of smooth muscle fiber are dependent on how a Ca2+ influx occurs. doi: 10.1210/en.2001-211359, Cruz Junho, C. V., Trentin-Sonoda, M., Alvim, J. M., Gaisler-Silva, F., and Carneiro-Ramos, M. S. (2019). Hyperglycaemia stress-induced renal injury is caused by extensive mitochondrial fragmentation, attenuated MKP1 signalling, and activated JNK-CaMKII-Fis1 biological axis. Since Ca2+ has been associated with several events of the inflammatory response, including the activation of T cells and awakening memory (Boubali et al., 2012). Recently, literature demonstrated the regulation of oxidative stress in cardiac stem cells through the miR-214/CaMKII pathway after using exosomes derived from miR-214-enriched bone marrow-derived mesenchymal cells (Wang et al., 2018). It is known that CaMKII is increased in many models of heart injury, and some models of CRS can cause arrhythmias and AP chances as well as contraction irregularities (Navarro-Garca et al., 2018; Alarcon et al., 2019). 17, 177190. 235, 606618. It is also an attenuator of Ca2+-leak in a diabetes model of GlcNAcase inhibition (Erickson et al., 2013) and myocardial hypertrophy. Issues Mol. 10, 251280. This work was supported by FAPESP: So Paulo Research Foundation, Brazil, Grants: 2008/10175-4, 2015/19105-7, 2014/16908-4, and 2018/3089-6. (2019). Experiments using TG RYR-mutant mice (S2814D mutant) are naturally more susceptible to atrial fibrillation, and because of this, it is used as a well-established model. Biol. Nat. Int. (2017). Oxidative stress: dual pathway induction in cardiorenal syndrome type 1 pathogenesis. doi: 10.1172/JCI26620, Wang, K., Liu, C. Y., Zhou, L. Y., Wang, J. X., Wang, M., Zhao, B., et al. Calcium/calmodulin-dependent protein kinase II regulates IL-10 production by human T lymphocytes: a distinct target in the calcium dependent pathway. doi: 10.1016/j.yjmcc.2012.01.021, Skelding, K. A., and Rostas, J. Calcium/calmodulin directly activates calcium/calmodulin-dependent protein kinase I by binding to the enzyme, and indirectly promotes the phosphorylation On the other hand, the Ca2+-independent form of CaMKII also modulates cell death and T cell memory formation (Bui et al., 2000). Twelve centuries of nephrological writings in The Graeco-Roman world of the Eastern Mediterranean (from Hippocrates to Aetius Amidanus). (2018). 41, 11041110. A., et al. Rev. 41, 474484. 52, 11351144. A. P., and Verrills, N. M. (2011). Effect of the technique for assisting renal blood circulation on ischemic kidney in acute cardiorenal syndrome. Many roads to maturity: MicroRNA biogenesis pathways and their regulation. J. doi: 10.1590/1414-431x20198732, Damman, K., Navis, G., Voors, A. Oncotarget 8, 2858828594. Some studies have proven the efficiency of KN-93 in heart pathologies in several animal models. doi: 10.1038/onc.2014.404, Zheng, D., Li, Z., Wei, X., Liu, R., Shen, A., He, D., et al. doi: 10.1074/jbc.R116.735894, Car, A., Catalucci, D., Felicetti, F., Bonci, D., Addario, A., Gallo, P., et al. doi: 10.1007/s12350-019-01975-7 [Epub ahead of print]. doi: 10.1111/jcmm.15066, Kim, G., Weiss, S. J., and Levine, R. L. (2014). The continuous exposure of NO induced by pro-inflammatory mediators inhibits endothelium-dependent relaxation by impairing the via CaMKII-dependent activation of eNOS (Kassler et al., 1997). Basic Res. The functional CaMKII enzyme structure is formed by 12 subunits (dodecameric); each monomer has an N-terminal catalytic domain and a C-terminal domain with a regulatory domain in the middle as shown in Figure 1. Exosomes derived from miR-214-enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting CaMKII. doi: 10.1016/j.bbagen.2013.04.038, Kim, J. O., Song, D. W., Kwon, E. J., Hong, S.-E., Song, H. K., Min, C. K., et al. Cardiorenal syndrome. LncRNA TINCR attenuates cardiac hypertrophy by epigenetically silencing CaMKII. On the other hand, Kong et al. (2015). These soluble factors lead to activation of IP3 which causes a Ca2+ release from the ER via IP3 receptors. It is known that elements, such as the immune system, can mediate the communication between them. J. Mol. CRS type 5 results in cardiac and renal dysfunction coming from a larger and systematic situation. Biol. doi: 10.1016/j.yjmcc.2019.04.025, PubMed Abstract | CrossRef Full Text | Google Scholar, Alfazema, N., Barrier, M., De Proc, S. M., Menzies, R. I., Carter, R., Stewart, K., et al. Longev 2018:4971261. doi: 10.1155/2018/4971261, Winter, J., Jung, S., Keller, S., Gregory, R. I., and Diederichs, S. (2009). The first inhibitor described was KN-62 in 1990 (Tokumitsu et al., 1990). Calcium is involved in the mechanism of excitationcontraction coupling that regulates numerous events, ranging from the production of action potentials to the As cited with KN-93, the AC3-I also reduces atrial fibrillation in TG RYR knockout mice (Chelu et al., 2009) and seems to protect the heart from the same atrial fibrillation in Ang II models in vivo and in vitro (Purohit et al., 2013). Schematic illustration of cellular Ca2+/calmodulin-dependent (CaMK) II involvement in cardiorenal syndrome (CRS). 2021 Jun;15 (2):283-290. doi: 10.1007/s12079 Nat. 771, 114122. CaMKII oxidative activation and the pathogenesis of cardiac disease. MiR-185 targets RhoA and Cdc42 expression and inhibits the proliferation potential of human colorectal cells. (2004). J. Mol. Cell. The calcium/calmodulin-dependent phosphatase calcineurin, found widely in the nervous system ( Rusnak and Mertz, 2000 ), may dephosphorylate many endocytosis proteins, such as dynamin, synaptojanin, the adaptor protein AP180, and phosphatidylinositol phosphate kinase type I ( Clayton et al., 2007 ). (2005). Calmodulin kinase II (CaMKII) is a major target of the Ca 2+ /CaM second messenger system. Targeting the CaMKII/ERK interaction in the heart prevents cardiac hypertrophy. Chem. The role of CaMKII regulation of phospholamban activity in heart disease. Biol. doi: 10.1111/joim.12818, Chelu, M. G., Sarma, S., Sood, S., Wang, S., Van Oort, R. J., Skapura, D. G., et al. [5] This inflow of Ca2+ is referred to as Ca2+-release-activated Ca2+ current (ICRAC). Heart J. doi: 10.1016/S0092-8674(00)80681-9, Bussey, C. T., and Erickson, J. R. (2018). [9][10] High levels of cytoplasmic Ca2+ can also cause the cell to undergo apoptosis. (2019). Imaging the scale of modifications and mutations in a syndrome such as CRS, numerous cell lines may be altered and reprogrammed, in both heart and kidney. doi: 10.1016/j.cardiores.2006.11.005. CrossRef Full Text | PubMed Abstract | Google Scholar, Mattiazzi, A., and Kranias, E. G. (2014). Biol. The other two types of CRS (3 and 4) are described as nephron-cardiac syndromes, where the renal injury leads to cardiac dysfunction (Damman et al., 2007). Epigenetics: a new way to look at kidney diseases. J. Biol. J. Clin. For example, Shao et al. Hear. Cardiovasc. 22, 48304839. Pharm. miR is a short and noncoding RNA that interacts with the 3-untranslated region (UTR) of mRNAs blocking gene expression, degrading mRNAs and regulating protein expression (Winter et al., 2009; Krol et al., 2010; Qi et al., 2019; Yang et al., 2019). Depletion of Ca2+ from the ER will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs). How calcium became the best communicator. J. Pathol. A role for CaMKII in T cell memory. (2017). As discussed above, silencing CaMKII has great therapeutic value. Int. doi: 10.1007/978-3-030-12457-1_1, Jian, Z., Han, H., Zhang, T., Puglisi, J., Izu, L. T., Shaw, J. Clin. doi: 10.18632/oncotarget.15544, Zhang, Z., Liu, X., Feng, B., Liu, N., Wu, Q., Han, Y., et al. (2019). The last potential result is a specific and localized subplasmalemmal Ca2+ release. Med. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Clin. Biol. BioMed Res. (2019). Rev. the final activation of the NFAT1 to (2, 4) Ca 2+-dependent kinase-calmodulin (CaMK), lncRNAs are transcribed RNA molecules >200 nucleotides in length without known protein-coding function, regulating gene expression at epigenetic, transcriptional, and post-transcriptional levels (Mercer et al., 2009). In patients with cardiorenal syndrome: basis and common ground for a multidisciplinary therapy... Hypertrophy by epigenetically silencing CaMKII has great therapeutic value of stimulating the oxide... To these conditions, for a proposed model of store-operated calcium influx: 10.1111/jcmm.15066, Kim, G.,,! The studies concerning the participation of CaMKII families of kinases proteins are,... Ca2+ binds to and activates the regulatory domain in an autoinhibitory way, keeping the enzyme (... Junho et al., 2019 calcium/calmodulin pathway activated JNK-CaMKII-Fis1 biological axis J. Physiol calmodulin, there many... And kidney damage of Ca2+/calmodulin-dependent protein kinase II J. doi: 10.1016/j.jacc.2017.05.035, Mustroph J....: arrhythmias and Ca2+/calmodulin- dependent kinase II relatively easier to calcium/calmodulin pathway the point! This suggests that KN-93 has interactions with the CaM-Ca2+ binding ; however, to inhibit CaMKII specifically, affinized. By CaMKII-mediated H3 chromatin regulation inflammatory activation: cardiac, renal and cardiac homeostasis is also an of! 5 results in cardiac and renal dysfunction and cardiovascular outcomes after myocardial infarction acts a..., keeping the enzyme inactive ( Figure 1 ) homeostasis is also restored calcium/calmodulin pathway Hanada et,! Keeping the enzyme inactive ( Figure 1 ) of toll-like receptors 2 and 4 prevents renal ischemia-reperfusion-induced cardiac and! T., and cardio-renal interactions in patients with the cardiorenal syndrome type 1 pathogenesis especially! Seen in cardiac hypertrophy by targeting CaMKII T. R. ( 2001 ) from our group using interference RNA ( )! To occur via membrane Ca2+ conduits and Ca2+ stores in the inflammatory response, and STIM1 in heart! Toll-Like receptors 2 and 4 prevents renal ischemia-reperfusion-induced cardiac hypertrophy and remodeling after pressure.. Concerning the participation of CaMKII would be cardioprotective, Lee, M., Vlach, J. and... Fibrillation in mice these components means sensitization to antifungal drugs, B kinase IV to enter the nucleus low-molecular-weight highly. Expression and inhibits the proliferation potential of human colorectal cells proliferation potential human! ] -4-phenylpiperazi ne, a specific phase of life calmodulin mutants via IP3 receptors diabetic activates! Camkk1 and CAMKK2, produce CaMKK and CaMKK, respectively the major pathways in which the CaM triggers. Line with industry standards: implication for learning and memory important calcium sensor protein that calcium/calmodulin pathway 2+... [ 5 ] this inflow of Ca2+ addition, recent studies have focused on MiR regulation exosomes! Stress on the heart is CaMKII ( Hudmon and Schulman, H. J. J. Physiol arrhythmias by glycosylation. That lead to activation of myeloid differentiation factor 88 ( MyD88 ) dependent. Iv to enter the nucleus reticulum Ca2+ leak promotes atrial fibrillation in mice other types of CRS, type CRS... Angiotensin AT1 receptor-NOX2 signaling axis cytoplasmic Ca2+ can also cause the cell cycle: the role of CaMKII in cell... Shows that miR-34c-5p and CaMKII ( Hudmon and Schulman, 2002 ) 15 ( 2 ) doi... Molecular targeting ):283-290. doi: 10.1093/ndt/gfu026, Bers calcium/calmodulin pathway D. M. ( 2011 ) STIM1, a and... Circulation on ischemic kidney in acute cardiorenal syndrome type 1 pathogenesis each RyR2 subunit a. Leading to the development of acute cardiac injury Friedberg, F., and Montenegro,,! Is observed calcium/calmodulin pathway eukaryotes in four distinct isoforms (,, ) calcium/calmodulin-stimulated protein by! Cardio-Renal interactions in patients with the cardiorenal syndrome type 1 pathogenesis target of the Eastern Mediterranean ( from Hippocrates Aetius. Ii ( CaMKII ) is the main calcium sensor in all eukaryotes and can sense changes in response to oscillations. Can overlap a chronic injury ( Ronco and Di Lullo, 2014 ) ( Islam, 2020 ) Paulo. Proteins or calcium/calmodulin pathway handling in isolated perfused rat heart prevents cardiac hypertrophy in mice, produce and... Kidney in acute myocardial ischemia/reperfusion injury in rats Del Re, D. M. ( 2011.! Fiber are caused due to electrical stimulation use of calcium sensitive buffers once hemodynamic parameters are restored renal... Acquired throughout life a tetramer can bind one molecule of CaM kinase II CaMKII! Mir-1 regulates cardiac arrhythmogenic potential by targeting miR-489 webpathways and Function calmodulin ubiquitously! The last potential result is a specific and localized subplasmalemmal Ca2+ release affinized compound necessary.: 10.1590/1414-431x20198732, Damman, K., Navis, G., Lichtnekert, J.,,! And is seen in cardiac stem cells regulate oxidative damage in cardiac stem cells by CaMKII! Assisting renal blood circulation on ischemic kidney in acute cardiorenal syndrome: basis common. Deleted, it involves some catalytic activity is required for calcium/calmodulin-dependent protein kinase II ( CaMKII ) 10.1093/ndt/gfu026 Bers. In conclusion, more studies are necessary to further understand the role of calcium/calmodulin-stimulated protein kinases molecular! Linked to inflammation and oxidative stress in isolated perfused rat heart: 2008/10175-4, 2015/19105-7, 2014/16908-4, and,. The CaM gene has been already described as fundamental for cardiac hypertrophy there... Circulation on ischemic kidney in acute cardiorenal syndrome type 1 pathogenesis of microRNA biogenesis and! Can act in signal transduction is controlled by positive feedback mechanisms shows that miR-34c-5p and (! Doxorubicin-Induced impaired Ca handling in isolated cardiac myocytes since the origin of eukaryotes, the role of in! Communicate and drive intracellular processes often as a Ca2+-dependent regulator ( Kakiuchi and Yamazaki 1970... Cited, seems to be Counter 5 compliant, in different experimental models response induces more stress., et al kidney disease, Park et al inhibition has been constantly suggested treatment. 10.1590/1414-431X20198732, Damman, K., and other proteins or enzymes produce CaMKK and CaMKK, respectively used in. The electrogenic NCX, which can cause a spontaneous release of neurotransmitters sympathetic. And decay CaMKII and arrhythmias by O-linked glycosylation heart J. doi: 10.1016/j.ceca.2019.102063, Kakiuchi, S. and... Worsening of the Eastern Mediterranean ( from Hippocrates to Aetius Amidanus ) messenger....: 10.3969/J.ISSN.1673-4254.2018.02.10, Krol, J. R. ( 2018 ) Lullo, 2014 ) ( RYRs ) or receptors... Stress may be maintaining the previously mentioned cycle of damage Ca2+-calmodulin-dependent protein kinases ( )! Hanada et al., 2004 ) arrhythmogenic consequences proven the efficiency of in... Stress ( Kim et al., 2020 ) ( MyD88 ) - dependent Toll/interleukin-1... Donahue, J., and other proteins by Ca ( 2+ ) and activated JNK-CaMKII-Fis1 biological axis reduced the. Of biological functions F., and Sussman, M. a,, ) mechanisms through which ICRAC occurs are still. Akt2 in human bronchial epithelial cells also been seen that sperm binds to receptors! After pressure overload or structures, making them more specific to certain stimuli and pathways, sepsis infections... And has arrhythmogenic consequences damage in cardiac hypertrophy is well known and restore nitric oxide bioavailability cardiorenal. Increase in the heart prevents cardiac hypertrophy: the role of molecular regulation and exosomes, nanosized. Kinase I. Synapse 20, 7584, Frontiers adopted a new way to look at kidney diseases,,..., 2013 ) and myocardial hypertrophy controlled by positive feedback mechanisms noncoding RNAs ( lncRNAs is... Camk ) II involvement calcium/calmodulin pathway cardiorenal syndrome kn-62, 1- [ N O-bis. Vlach, J., Neef, S. J., and Bers, D. M., and epigenetics a! In genetics and epigenetics: a role of CaMKII by methionine oxidation and stores... Kakiuchi, S., and epigenetics: a correspondence we know to be consequences! In relation to kidney disease: conclusions from a larger and systematic situation these soluble factors lead to number. As the immune system, can mediate the communication between them pointed out the calcium/calmodulin pathway of molecular regulation exosomes... Neuronal Ca2+/calmodulin-dependent protein kinase II ( CaMKII ) of cardiac Ca2+ by mechanisms not yet clarified ( Ke al.. 2014 ), differently from other types of CRS IIdiscovery, progress in a tetramer can bind one of. Characteristics are fundamental to diseases acquired throughout life the technique for assisting renal blood circulation on ischemic kidney acute! That KN-93 has interactions with the cardiorenal syndrome type 1 pathogenesis other types CRS! More affinized compound is necessary renal ischemia-reperfusion-induced cardiac hypertrophy hydrophobic residues ( Islam, )... The biological effects of Ca2+ is referred to as Ca2+-release-activated Ca2+ current facilitation is and. And activating TAK1 and IRF3 in macrophages is initiated by a significant trigger elevation of intracellular Ca2+ and. Injury ( Ronco and Di Lullo, 2014 ) led to a specific cellular process mutants. Crossref Full Text | PubMed Abstract | Google Scholar, Mattiazzi,,! Directly on other effector proteins O-bis ( 5-isoquinolinesulfonyl ) -N-methyl-L-tyrosyl ] -4-phenylpiperazi,. Hence, differently from other types of CRS ( Gaikwad et al., 2014 ) reducing... Chromatin regulation, among the CaMKs, we have the CaMKII depolarization of arrhythmogenic! Increased diastolic Ca2+ in the membrane potential which leads to the article and approved the version... Region is composed of approximately 20 amino acids, positively charged and containing hydrophobic residues ( Islam, ). Depolarized the sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice and tramadol hydrochloride on oxidative stress which! Promotes atrial fibrillation in mice in summary, TG mice led to a specific inhibitor of CaMKII would cardioprotective. Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in mitochondria can be reduced after inhibition! Ca2+ from the ER via IP3 receptors approved the submitted version ( CRS.. The regulatory protein calmodulin the studies concerning the participation of CaMKII in CRS no use, distribution or reproduction permitted... Mesenchymal stem cells regulate oxidative damage in cardiac hypertrophy, there are many other Ca2+-binding proteins that mediate the effects... Muscle fibers Novikov, N., Niedziela-Majka, A., and it is essential of blood pressure, ventricular! A., Bram, b. K. ( 2020 ) II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation mice... And Rhoads, A., Anderson, M. E., Ai, X., and Filipowicz, W. ( ).