CaMKIIdelta Subtypes: Localization and Function

Overview

Journal Front Pharmacol

Date 2014 Feb 28

PMID 24575042

Citations 46

Authors

Charles B B Gray

Joan Heller Brown

Affiliations

Soon will be listed here.

Abstract

In this review we discuss the localization and function of the known subtypes of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and their role in cardiac physiology and pathophysiology. The CaMKII holoenzyme is comprised of multiple subunits that are encoded by four different genes called CaMKIIα, β, γ, and δ. While these four genes have a high degree of sequence homology, they are expressed in different tissues. CaMKIIα and β are expressed in neuronal tissue while γ and δ are present throughout the body, including in the heart. Both CaMKIIγ and δ are alternatively spliced in the heart to generate multiple subtypes. CaMKIIδ is the predominant cardiac isoform and is alternatively spliced in the heart to generate the CaMKIIδB subtype or the slightly less abundant δC subtype. The CaMKIIδB mRNA sequence contains a 33bp insert not present in δC that codes for an 11-amino acid nuclear localization sequence. This review focuses on the localization and function of the CaMKIIδ subtypes δB and δC and the role of these subtypes in arrhythmias, contractile dysfunction, gene transcription, and the regulation of Ca(2+) handling.

Citing Articles

The CaMK Family Differentially Promotes Necroptosis and Mouse Cardiac Graft Injury and Rejection.

Lu H, Jiang J, Min J, Huang X, McLeod P, Liu W Int J Mol Sci. 2024; 25(8).

PMID: 38674016 PMC: 11050252. DOI: 10.3390/ijms25084428.

CAMK2D serves as a molecular scaffold for RNF8-MAD2 complex to induce mitotic checkpoint in glioma.

Chuah Y, Tay E, Grinchuk O, Yoon J, Feng J, Kannan S Cell Death Differ. 2023; 30(8):1973-1987.

PMID: 37468549 PMC: 10406836. DOI: 10.1038/s41418-023-01192-3.

CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report.

Tolmacheva E, Shubina J, Kochetkova T, Ushakova L, Bokerija E, Vasiliev G Genes (Basel). 2023; 14(6).

PMID: 37372357 PMC: 10298453. DOI: 10.3390/genes14061177.

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca.

Terrar D Philos Trans R Soc Lond B Biol Sci. 2023; 378(1879):20220170.

PMID: 37122228 PMC: 10150226. DOI: 10.1098/rstb.2022.0170.

Statins Protect Against Early Stages of Doxorubicin-induced Cardiotoxicity Through the Regulation of Akt Signaling and SERCA2.

Dadson K, Thavendiranathan P, Hauck L, Grothe D, Azam M, Stanley-Hasnain S CJC Open. 2022; 4(12):1043-1052.

PMID: 36562012 PMC: 9764135. DOI: 10.1016/j.cjco.2022.08.006.

References

Ling H, Gray C, Zambon A, Grimm M, Gu Y, Dalton N . Ca2+/Calmodulin-dependent protein kinase II δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κB. Circ Res. 2013; 112(6):935-44. PMC: 3673710. DOI: 10.1161/CIRCRESAHA.112.276915. View

Maltsev V, Sabbah H, Higgins R, Silverman N, Lesch M, Undrovinas A . Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation. 1998; 98(23):2545-52. DOI: 10.1161/01.cir.98.23.2545. View

Little G, Saw A, Bai Y, Dow J, Marjoram P, Simkhovich B . Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in cardiomyocyte survival in cardiomyopathy. J Biol Chem. 2009; 284(37):24857-68. PMC: 2757189. DOI: 10.1074/jbc.M109.003186. View

Tobimatsu T, Fujisawa H . Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs. J Biol Chem. 1989; 264(30):17907-12. View

Huke S, DeSantiago J, Kaetzel M, Mishra S, Brown J, Dedman J . SR-targeted CaMKII inhibition improves SR Ca²+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC. J Mol Cell Cardiol. 2010; 50(1):230-8. PMC: 3018844. DOI: 10.1016/j.yjmcc.2010.10.014. View

Krainer A, Maniatis T . Multiple factors including the small nuclear ribonucleoproteins U1 and U2 are necessary for pre-mRNA splicing in vitro. Cell. 1985; 42(3):725-36. DOI: 10.1016/0092-8674(85)90269-7. View

Yamauchi T, Ohsako S, Deguchi T . Expression and characterization of calmodulin-dependent protein kinase II from cloned cDNAs in Chinese hamster ovary cells. J Biol Chem. 1989; 264(32):19108-16. View

Wu Y, Temple J, Zhang R, Dzhura I, Zhang W, Trimble R . Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation. 2002; 106(10):1288-93. DOI: 10.1161/01.cir.0000027583.73268.e7. View

Heist E, Srinivasan M, Schulman H . Phosphorylation at the nuclear localization signal of Ca2+/calmodulin-dependent protein kinase II blocks its nuclear targeting. J Biol Chem. 1998; 273(31):19763-71. DOI: 10.1074/jbc.273.31.19763. View

10.

Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor S . A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003; 111(10):1497-504. PMC: 155051. DOI: 10.1172/JCI17664. View

11.

Anderson M, Braun A, Lu T, Wu Y, Schulman H, Sung R . KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. J Pharmacol Exp Ther. 1998; 287(3):996-1006. View

12.

Elrod J, Wong R, Mishra S, Vagnozzi R, Sakthievel B, Goonasekera S . Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J Clin Invest. 2010; 120(10):3680-7. PMC: 2947235. DOI: 10.1172/JCI43171. View

13.

Colomer J, Mao L, Rockman H, Means A . Pressure overload selectively up-regulates Ca2+/calmodulin-dependent protein kinase II in vivo. Mol Endocrinol. 2003; 17(2):183-92. DOI: 10.1210/me.2002-0350. View

14.

Mayer P, Mohlig M, Idlibe D, Pfeiffer A . Novel and uncommon isoforms of the calcium sensing enzyme calcium/calmodulin dependent protein kinase II in heart tissue. Basic Res Cardiol. 1995; 90(5):372-9. DOI: 10.1007/BF00788498. View

15.

Jia C, Li M, Liu J, Zhao L, Lin J, Lai P . IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1. Cell Death Differ. 2012; 20(2):248-58. PMC: 3554328. DOI: 10.1038/cdd.2012.115. View

16.

Zhu W, Woo A, Yang D, Cheng H, Crow M, Xiao R . Activation of CaMKIIdeltaC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis. J Biol Chem. 2007; 282(14):10833-9. DOI: 10.1074/jbc.M611507200. View

17.

Bennett M, Erondu N, Kennedy M . Purification and characterization of a calmodulin-dependent protein kinase that is highly concentrated in brain. J Biol Chem. 1983; 258(20):12735-44. View

18.

Lu Y, Huang J, Shioda N, Fukunaga K, Shirasaki Y, Li X . CaMKIIδB mediates aberrant NCX1 expression and the imbalance of NCX1/SERCA in transverse aortic constriction-induced failing heart. PLoS One. 2011; 6(9):e24724. PMC: 3172303. DOI: 10.1371/journal.pone.0024724. View

19.

Koval O, Snyder J, Wolf R, Pavlovicz R, Glynn P, Curran J . Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease. Circulation. 2012; 126(17):2084-94. PMC: 3811023. DOI: 10.1161/CIRCULATIONAHA.112.105320. View

20.

Ji Y, Li B, Reed T, Lorenz J, Kaetzel M, Dedman J . Targeted inhibition of Ca2+/calmodulin-dependent protein kinase II in cardiac longitudinal sarcoplasmic reticulum results in decreased phospholamban phosphorylation at threonine 17. J Biol Chem. 2003; 278(27):25063-71. DOI: 10.1074/jbc.M302193200. View