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Abstract
Ion channels and Ca2+-handling proteins involved in the regulation of cardiac electrophysiology and contractility are organized in macromolecular multiprotein complexes. Recent molecular and cellular studies have significantly enhanced our understanding of the composition of these macromolecular complexes and have helped to elucidate their role in the dynamic regulation of ion channel function. Moreover, it has become clear that alterations in the composition of ion channel macromolecular complexes, for example, due to genetic mutations or acquired alterations in the expression of individual components, may lead to ion channel dysfunction and arrhythmogenesis. Here, we review novel insights into the composition of the major ion channel macromolecular complexes and discuss the potential clinical significance of alterations in these dynamic multiprotein structures.
Highlights
Every heartbeat is orchestrated by a cascade of electrical activity that initiates contraction in cardiomyocytes through a process termed excitation–contraction coupling [1, 2]
The tightly controlled regulation of ion channel function plays a critical role in cardiacphysiology
Macromolecular complexes are essential for this regulation by bringing together poreforming and regulatory subunits, proteins controlling ion channel trafficking and localization, kinases, phosphatases and other components of signaling pathways, as well as proteins involved in other forms of ion channel regulation (e. g., Ca2+-dependent regulation)
Summary
Every heartbeat is orchestrated by a cascade of electrical activity that initiates contraction in cardiomyocytes through a process termed excitation–contraction coupling [1, 2]. Research performed during the past 20 years has shown that the ion channels and Ca2+-handling proteins that are essential for cardiomyocyte electrophysiology and excitation–contraction coupling are organized in large macromolecular multiprotein complexes [3]. Na+ and K+ concentrations is achieved via the Na+-K+-ATPase Each of these ion channels is a large macromolecular complex consisting of numerous proteins that regulate the intracellular movement and distribution (a processes termed trafficking) and function of these channels. At least a dozen regulatory subunits have been identified as part of the RyR2 macromolecular complex [1, 10], including FK506 binding protein 12.6 (FKBP12.6), which enhances cooperation between the four pore-forming α subunits, regulating the stability of the channel’s closed state.
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