Altered Na⁺ channel activity and reduced Cl⁻ conductance cause hyperexcitability in recessive generalized myotonia (becker)

Abstract

Intact muscle fibers or resealed fiber segments from 7 patients with recessive generalized myotonia were studied in vitro. All fibers had normal resting membrane potentials and normal resting [Ca2+]i several hours after removal. Contractions were characterized by slowed relaxation which was due to electrical after-activity. Often spontaneous depolarizations were recorded intracellularly. In all fibers, the steady state voltage-current relationship was abnormal, due to a reduced Cl- conductance. However, this conductance ranged from 0% to 66% of the total membrane conductance, whereas, in normal muscle, it was 80%. Theoretically, myotonic after-discharges would not appear until the Cl- conductance is below 20%. Thus, the membrane hyperexcitability must be due to another defect, at least in the preparations in which the Cl- conductance was only slightly reduced. In all patches from all patients investigated with the patch clamp technique, we observed reopenings of the Na+ channels throughout depolarizing pulses (such behavior was absent in normal muscle). If a patch was polarized to potentials less negative than the resting potential, the duration of the reopenings increased. We conclude that a combination of reduced Cl- conductance and the reopenings of Na+ channels underlie the electrical after-activity in recessive generalized myotonia.

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia

“…The main cause underlying MC is a reduced sarcolemmal chloride conductance. 2,3 Thomsen's and Becker's myotonia have both been shown to be associated with mutations in the skeletal muscle chloride channel gene, CLCN1, which encodes the major skeletal muscle chloride channel, ClC-1. 4 CLCN1 maps to chromosome 7q35, and is organised in 23 exons.…”

The CLC chloride channel family

“…ClC-1 is activated by depolarization, has a Cl>I ion selectivity and a small single-channel conductance of 1-2 pS [96], and is sensitive to extra-and intracellular pH [25,101,102]. Previous studies had shown that there is a decrease in skeletal muscle chloride conductance in certain forms of myotonia, both in humans [32,68] as well as in animal models [8,83]. Thus, ClC-1 was an excellent candidate gene for myotonia.…”

Age‐dependent chloride channel expression in skeletal muscle fibres of normal and HSALR myotonic mice

“…However, there is considerable evidence suggesting that myotonia may not exclusively result from a sarcolemma‐restricted chloride channelopathy, but that non‐linear properties of ClC‐1 and/or other ion channels (especially in the TTS membranes) may contribute to, or even cause, the pathology (Adrian & Bryant, 1974; Aromataris & Rychkov, 2006). For example, human congenital (non‐dystrophic) myotonias and DM1 have been explained on the basis of alterations of Na channels (Franke et al . 1990, 1991; Iaizzo et al .…”