title: The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle.
abstract: A novel category of diseases of striated muscle is proposed, the couplonopathies, as those that affect components of the couplon and thereby alter its operation. Couplons are the functional units of intracellular calcium release in excitation-contraction coupling. They comprise dihydropyridine receptors, ryanodine receptors (Ca2+ release channels), and a growing list of ancillary proteins whose alteration may lead to disease. Within a generally similar plan, the couplons of skeletal and cardiac muscle show, in a few places, marked structural divergence associated with critical differences in the mechanisms whereby they fulfill their signaling role. Most important among these are the presence of a mechanical or allosteric communication between voltage sensors and Ca2+ release channels, exclusive to the skeletal couplon, and the smaller capacity of the Ca stores in cardiac muscle, which results in greater swings of store concentration during physiological function. Consideration of these structural and functional differences affords insights into the pathogenesis of several couplonopathies. The exclusive mechanical connection of the skeletal couplon explains differences in pathogenesis between malignant hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia (CPVT), conditions most commonly caused by mutations in homologous regions of the skeletal and cardiac Ca(2+) release channels. Based on mechanistic considerations applicable to both couplons, we identify the plasmalemma as a site of secondary modifications, typically an increase in store-operated calcium entry, that are relevant in MH pathogenesis. Similar considerations help explain the different consequences that mutations in triadin and calsequestrin have in these two tissues. As more information is gathered on the composition of cardiac and skeletal couplons, this comparative and mechanistic approach to couplonopathies should be useful to understand pathogenesis, clarify diagnosis, and propose tissue-specific drug development.
authors.affiliation: Section of Cellular Signaling, Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612 erios@rush.edu.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ríos
authors.affiliation: Section of Cellular Signaling, Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Figueroa
authors.affiliation: Section of Cellular Signaling, Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612.
authors.forename: Carlo
authors.initials: C
authors.lastname: Manno
authors.affiliation: Malignant Hyperthermia Investigation Unit, University Health Network, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kraeva
authors.affiliation: Malignant Hyperthermia Investigation Unit, University Health Network, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Sheila
authors.initials: S
authors.lastname: Riazi
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D056966:Excitation Contraction Coupling; D020022:Genetic Predisposition to Disease; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D002155:Calsequestrin; D002352:Carrier Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C070048:triadin