Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

Abstract

The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this Jeng et al.ClC-1 Proteostasis and Myotonia chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy

“…For example, in direct contrast to the universally expressed hyperpolarization-activated ClC-2 channel, the ClC-1 channel is specifically expressed in skeletal muscles and activated by membrane depolarization. Loss-of-function mutations in the human CLCN1 gene that instigate defective gating and proteostasis of the ClC-1 channel have been associated with the hereditary muscle disease myotonia congenita [ 5 , 63 ]. Interestingly, we previously demonstrated that ClC-1 WT and disease-causing mutant proteins are also subject to polyubiquitination and degradation by the CUL4-DDB1-CRBN E3 ubiquitin ligase [ 64 ].…”

Changes in Expression and Cellular Localization of Rat Skeletal Muscle ClC-1 Chloride Channel in Relation to Age, Myofiber Phenotype and PKC Modulation

“…The mutations of ClC-1 associated with myotonia congenita can be correlated to anomalous gating-permeation or reduced ClC-1 protein abundance at the plasma membrane (Lee et al, 2013;Jeng et al, 2020). This distinction, together with the new and important advance in knowledge of the mechanisms behind proteostasis (Peng et al, 2016), biogenesis (Chen et al, 2015) and those governing trafficking to the surface membrane (Peng et al, 2018), has opened the doors to the novel pharmacological approach for increasing ClC-1 in plasma membrane (Altamura et al, 2018;Jeng et al, 2020). By studying the biophysical mechanism to induce an increase of ClC-1 in plasma membrane, certain inhibitors of ligase E3 (Lee et al, 2013) or blockers of ubiquitin inhibitors (Chen et al, 2015) are emerging.…”

The Pump-Leak/Donnan ion homeostasis strategies of skeletal muscle fibers and neurons

“…CD modeling comparisons here highlight two overlooked facets of SMF physiology: 1) the collaboration of ClC-1 channels with Donnan effectors is imperative for SMF ion homeostasis (not just for low SMF excitability (Jentsch and Pusch, 2018; Jeng et al 2020) and 2) the extraordinary smallness of the (unidentified) SMF P Na renders it pivotal (via its [small I Naleak ]) to the robustness of SMF ion homeostasis.…”