6bab

Structural highlights

Function

[KCC2D_MOUSE] Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor.^{[1] [2] [3] [4] [5] [6] [7]}

References

1. ↑ Zhang T, Maier LS, Dalton ND, Miyamoto S, Ross J Jr, Bers DM, Brown JH. The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res. 2003 May 2;92(8):912-9. doi: 10.1161/01.RES.0000069686.31472.C5. Epub, 2003 Apr 3. PMID:12676814 doi:http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5
2. ↑ Sergeant GP, Ohya S, Reihill JA, Perrino BA, Amberg GC, Imaizumi Y, Horowitz B, Sanders KM, Koh SD. Regulation of Kv4.3 currents by Ca2+/calmodulin-dependent protein kinase II. Am J Physiol Cell Physiol. 2005 Feb;288(2):C304-13. doi:, 10.1152/ajpcell.00293.2004. Epub 2004 Sep 29. PMID:15456698 doi:http://dx.doi.org/10.1152/ajpcell.00293.2004
3. ↑ Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE Jr, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med. 2005 Apr;11(4):409-17. doi: 10.1038/nm1215. Epub 2005 Mar 27. PMID:15793582 doi:http://dx.doi.org/10.1038/nm1215
4. ↑ Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz L, Kirchhof P, Maier SK, Zhang T, Hasenfuss G, Brown JH, Bers DM, Maier LS. Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest. 2006 Dec;116(12):3127-38. doi: 10.1172/JCI26620. Epub 2006 Nov 22. PMID:17124532 doi:http://dx.doi.org/10.1172/JCI26620
5. ↑ Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick DM, Grueter CE, Qi X, Richardson JA, Hill JA, Katus HA, Bassel-Duby R, Maier LS, Olson EN. The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2342-7. doi:, 10.1073/pnas.0813013106. Epub 2009 Jan 28. PMID:19179290 doi:http://dx.doi.org/10.1073/pnas.0813013106
6. ↑ Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y, Dalton ND, Peterson KL, Chen J, Bers D, Brown JH. Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest. 2009 May;119(5):1230-40. doi: 10.1172/JCI38022. Epub 2009 Apr 20. PMID:19381018 doi:http://dx.doi.org/10.1172/JCI38022
7. ↑ Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, Grumbach IM, Luczak ED, Colbran RJ, Song LS, Hund TJ, Mohler PJ, Anderson ME. CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4996-5000. doi:, 10.1073/pnas.0913760107. Epub 2010 Mar 1. PMID:20194790 doi:http://dx.doi.org/10.1073/pnas.0913760107