When muscle Ca²⁺ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis

Abstract

Patients suffering from type 1 hypokalaemic periodic paralysis (HypoPP1) experience attacks of muscle paralysis associated with hypokalaemia. The disease arises from missense mutations in the gene encoding the α1 subunit of the dihydropyridine receptor (DHPR), a protein complex anchored in the tubular membrane of skeletal muscle fibres which controls the release of Ca from sarcoplasmic reticulum and also functions as a Ca channel. The vast majority of mutations consist of the replacement of one of the outer arginines in S4 segments of the α1 subunit by neutral residues. Early studies have shown that muscle fibres from HypoPP1 patients are abnormally depolarized at rest in low K to the point of inducing muscle inexcitability. The relationship between HypoPP1 mutations and depolarization has long remained unknown. More recent investigations conducted in the closely structurally related voltage-gated Na and K channels have shown that comparable S4 arginine substitutions gave rise to elevated inward currents at negative potentials called gating pore currents. Experiments performed in muscle fibres from different models revealed such an inward resting current through HypoPP1 mutated Ca channels. In mouse fibres transfected with HypoPP1 mutated channels, the elevated resting current was found to carry H for the R1239H arginine-to-histidine mutation in a S4 segment and Na for the V876E HypoPP1 mutation, which has the peculiarity of not being located in S4 segments. Muscle paralysis probably results from the presence of a gating pore current associated with hypokalaemia for both mutations, possibly aggravated by external acidosis for the R1239H mutation.

Divalent cations permeation in a Ca2+ non-conducting skeletal muscle dihydropyridine receptor mouse model

“…Very few data on Cav1.1 structure-function relationship are available in fully differentiated skeletal muscle fibers, except in the context of muscle diseases for which genetically engineered mouse models have been generated or mutated Cav1.1 have been transfected [26]. Also, it is always questionable if data obtained in cultured muscle cells or in heterologous expression systems, which, moreover, is only recently possible, are transferable to fully differentiated skeletal muscle fibers [27].…”

Measurement of intracellular ion activity in skeletal muscle fibers: Four microelectrodes or no deal

“…The absolute changes of activity of these ions are poorly characterized at rest, in activity, and possibly during cell stretching and therefore deserve to be scrutinized. The use of this method should be also essential for exploring perturbations of ion activity that have been suggested to exist in a number of muscle channelopathies including periodic paralysis (Cannon, 2015;Allard and Fuster, 2018). Finally, one may hope that this study will contribute to the dissemination of muscle electrophysiology, which unfortunately has become scarce, and help muscle physiologists realize how critical it is to control voltage when investigating the movements of ions including the ubiquitous Ca 2+ ion.…”

Evaluation of mutant muscle Ca2+ channel properties using two different expression systems

“…Apart from two mutations—one localized in the S3 segment of domain III (V876E) and one in the S4-S5 loop of domain III (H916Q)—all HypoPP1 mutations consist of a substitution of the first or second outermost basic residue with a less charged amino acid (histidine, serine, or glycine) in the voltage-sensing S4 segment of domain II (R528H/G), domain III (R897S, R900S), or domain IV (R1239H/G) (Cannon, 2010; Matthews and Hanna, 2010; Jurkat-Rott et al, 2012; Moreau et al, 2014; Allard and Fuster, 2018). Long before the identification of HypoPP1 mutations (Jurkat-Rott et al, 1994; Ptácek et al, 1994), early experiments performed in muscle fibers from HypoPP1 patients’ muscle biopsies had shown that diseased muscle cells were abnormally depolarized in low K + external solution to the point of rendering cells inexcitable (Rüdel et al, 1984; Ruff, 1999).…”

“…Along this line, the STAC3-coexpressed Cav1.1 L-type Ca 2+ current in oocytes was not found to inactivate in response to maintained depolarization, whereas a well identified voltage-dependent inactivation mechanism is known to occur in fully differentiated muscle fibers (Collet et al, 2003; Ursu et al, 2004). The presence of a native muscle environment for the transfected channel is the main advantage of the in vivo mouse model system (Fuster et al, 2017a,b; Allard and Fuster, 2018). Inversely, in this system, the endogenous mouse Ca 2+ channels are not entirely replaced by the transfected channels so that the biophysical properties of the Ca 2+ channel inevitably correspond to a mixture of the biophysical properties of endogenous and transfected channels.…”