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.

Figure 1.

Sites of Ca²⁺ release in skeletal and cardiac muscle. (A and B) Transversal and longitudinal sections of a skeletal muscle triad junction. TC, terminal cisternae. (C) Transversal section of junctions in a cardiac myocyte, between a larger transverse tubule (TT) and very narrow SR cisternae. (D) Protein-filled vesicles (presumably dilated cisternae) in cardiomyocytes of mouse overexpressing calsequestrin 2, to demonstrate that the volume differences are largely determined by the quantity of calsequestrin. A and B show unpublished images by C. Franzini-Armstrong. C and D show images modified from Jones et al. (1998) with permission from The American Society for Clinical Investigation, Inc.

Figure 2.

Diagrammatic view of couplons. (A) In skeletal muscle, a double row of RyR1 channels in SR membrane faces tetrads of DHPRs in transverse tubule membrane in a pattern consistent with mechanical contact between DHPRs and alternate RyRs in each row. RyRs are bound to triadin (Tr) and junctin (Jn), transmembrane proteins which link to calsequestrin inside the SR (Casq). Formation of linear ramified polymers of Casq is promoted by Ca²⁺ (dots). The SR protein JP-45 links DHPRs to Casq, bypassing the RyR. (B) In cardiac muscle, the DHPRs of plasmalemma and transverse tubules neither form tetrads nor connect mechanically with RyRs. These are placed in multiple rows, which form clusters of variable size and shape. Linkage of RyR to calsequestrin by Tr and Jn is depicted identically in both tissues, but the cytosolic segment of cardiac Tr is shorter. The cartoon also reflects the absence of JP-45 in cardiac muscle. Other proteins that bind to RyR and Casq are omitted. Allosteric interactions, verified or putative, are represented by arrows. In A, double arrow 1 represents the two-way “longitudinal” interaction between DHPRs and RyRs present in skeletal muscle. The arrows in B represent actions proposed for both tissues: the “transversal” interaction between RyRs is indicated by arrow 2, whereas arrows 3 depict possible [Ca²⁺]_SR-dependent conformational effects of calsequestrin on RyR channels. See additional details in section “Skeletal and cardiac couplons are different.”

Figure 3.

Perchlorate as a couplon agonist. (A) The EC coupling transfer function; relationship between amount of voltage sensor charge displaced and peak Ca²⁺ release flux (measured in voltage-clamped cell of the frog semitendinosus muscle). Perchlorate linearizes the relationship in a dose-dependent manner. (B) An allosteric model, which uses the MWC formalism to describe the activation of release channel opening (represented by the transition from states C_j to O_j) by the operation of four voltage sensors (circles); upon membrane depolarization these move to the activating position (represented as +) in a sequence progressing from left to right. The model reproduces many features of Ca²⁺ release activation, including the effects of perchlorate. This anion is assumed to increase the single parameter f, which embodies the activating effect of each moving voltage sensor. Changes in the transfer function (represented in C) and charge displacement then ensue. Panels are modified from Ríos et al. (1993).