Abstract
Calmodulin (CaM) is the principal Ca2+ sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes that encode identical CaM proteins lead to major cardiac dysfunction, revealing the importance in the regulation of excitability. In turn, some mutations at the CaM binding site of ion channels cause similar diseases. Here we provide a summary of the two sides of the partnership between CaM and ion channels, describing the diversity of consequences of mutations at the complementary CaM binding domains.
Highlights
Calcium is a universal signaling messenger involved in fundamental processes, including muscle contraction, long-term potentiation, apoptosis, or cell proliferation [1,2]
Both currents are Ca2+-dependent and genetic analysis demonstrated that defects on the sole CaM gene in Paramecium were responsible for both phenotypes [8]
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is most commonly caused by gain-of-function RyR2 mutations with excessive Ca2+ release [42,43] or mutations affecting RyR2-binding proteins [19,44], which lead to spontaneous opening and Ca2+ waves that trigger membrane depolarization
Summary
Calcium is a universal signaling messenger involved in fundamental processes, including muscle contraction, long-term potentiation, apoptosis, or cell proliferation [1,2]. Since Ca2+ is toxic to the cell, signaling by this cation has to be brief and tightly controlled [2]. Different mechanisms lead to transient intracellular increases in Ca2+ concentrations that initiate different protein activities. The ability to transmit conformational changes to a large and diverse array of proteins in response to Ca2+ oscillations, coordinating the activity of hundreds of proteins, makes calmodulin (CaM, see a list of Abbreviations) the most important Ca2+ signal transducer in eukaryotic cells. The ability to bind and regulate such a large and diverse array of proteins resides in its inherent flexible nature that allows to fit structurally into more than 300 target proteins and to trigger diverse regulatory mechanisms
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