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 Ca2+ 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.

Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy

“…(i) A syndrome similar to malignant hyperthermia (MH) has been reported for Casq1-null mice (17,18). The causation of MH by Casq1 absence is consistent with the observations in cardiac muscle as both are mechanistically similar diseases of enhancement and loss of control of Ca 2ϩ release (19), and polymorphic ventricular tachycardia is, in most cases, associated with severe deficits in the amount of protein present (16). (ii) A missense mutation, D244G, is linked to a myopathy characterized by the presence of vacuoles containing SR protein inclusions (20).…”

“…Some evidence indi-cates that Casq is required for adequate channel closure in skeletal muscle (13,14), but the issue remains controversial (15). Much of the interest in the properties of this protein stems from observations of linkage between its mutations and human disease (special cases of "couplonopathies" or diseases of the couplon (19)). This association is especially clear in the heart where at least 15 Casq2 mutations have been linked with a disease known as catecholaminergic polymorphic ventricular tachycardia (for a review, see Ref.…”

Calsequestrin depolymerizes when calcium is depleted in the sarcoplasmic reticulum of working muscle

“…As crucial as polymerization appears to be for storage, and putatively other functions, its corollary, depolymerization, has never been demonstrated in a working cell upon depletion of the calcium store. Depolymerization would not just alter the buffer function of the protein; given the mechanical link of calsequestrin with other proteins in the couplon (15,16), including the calcium release channels of the SR (RyRs), depolymerization could be sensed as an allosteric signal by the RyRs, thereby providing a physical mechanism for their control. Depolymerization would derail the hypothetical diffusional enhancement by destroying the calcium wires; it might also allow migration of calsequestrin away from triads, with damaging targeting and functional repercussions.…”

Overactivation of the sodium–calcium exchanger and transient receptor potential in anesthesia‐induced malignant hyperthermia

“…Mutant gene CACNA1S(19) and stac3 are additionally connected with MH susceptibleness (MHS) . The expanded defectiveness of the RyR (Ryanodine receptors) is endured by the muscle, potentially because of adjustments in the manner the t‐framework handles Ca 2+ . This could be because of changes in the limit of: (a) store‐worked Ca 2+ passage, a Ca 2+ influx pathway controlled by [Ca 2+ ]SR, as well as (b) alterations in the expulsion of Ca 2+ from the cytoplasm to the t‐framework lumen by PMCA and NCX (Figure ).…”