Calmodulin kinase is a molecular switch for cardiac excitation-contraction coupling.
Signaling between cell membrane-bound L-type Ca(2+) channels (LTCC) and ryanodine receptor Ca(2+) release channels (RyR) on sarcoplasmic reticulum (SR) stores grades excitation-contraction coupling (ECC) in striated muscle. A physical connection regulates LTCC and RyR in skeletal muscle, but the molecular mechanism for coordinating LTCC and RyR in cardiomyocytes, where this physical link is absent, is unknown. Calmodulin kinase (CaMK) has characteristics suitable for an ECC coordinating molecule: it is activated by Ca(2+)/calmodulin, it regulates LTCC and RyR, and it is enriched in the vicinity of LTCC and RyR. Intact cardiomyocytes were studied under conditions where CaMK activity could be controlled independently of intracellular Ca(2+) by using an engineered Ca(2+)-independent form of CaMK and a highly specific CaMK inhibitory peptide. CaMK reciprocally enhanced L-type Ca(2+) current and reduced release of Ca(2+) from the SR while increasing SR Ca(2+) content. These findings support the hypothesis that CaMK is required to functionally couple LTCC and RyR during cardiac ECC.
Wu
Y
Y
Department of Internal Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Colbran
R J
RJ
Anderson
M E
ME
D000595:Amino Acid Sequence; D000814:Aniline Compounds; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005456:Fluorescent Dyes; D006321:Heart / Q000502:physiology*; D009200:Myocardial Contraction; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction; D014966:Xanthenes
D000814:Aniline Compounds; D020746:Calcium Channels, L-Type; D005456:Fluorescent Dyes; D019837:Ryanodine Receptor Calcium Release Channel; D014966:Xanthenes; C059715:Fluo-3; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium