Role of physiological ClC-1 Cl− ion channel regulation for the excitability and function of working skeletal muscle

Abstract

Electrical membrane properties of skeletal muscle fibers have been thoroughly studied over the last five to six decades. This has shown that muscle fibers from a wide range of species, including fish, amphibians, reptiles, birds, and mammals, are all characterized by high resting membrane permeability for Cl− ions. Thus, in resting human muscle, ClC-1 Cl− ion channels account for ∼80% of the membrane conductance, and because active Cl− transport is limited in muscle fibers, the equilibrium potential for Cl− lies close to the resting membrane potential. These conditions—high membrane conductance and passive distribution—enable ClC-1 to conduct membrane current that inhibits muscle excitability. This depressing effect of ClC-1 current on muscle excitability has mostly been associated with skeletal muscle hyperexcitability in myotonia congenita, which arises from loss-of-function mutations in the CLCN1 gene. However, given that ClC-1 must be drastically inhibited (∼80%) before myotonia develops, more recent studies have explored whether acute and more subtle ClC-1 regulation contributes to controlling the excitability of working muscle. Methods were developed to measure ClC-1 function with subsecond temporal resolution in action potential firing muscle fibers. These and other techniques have revealed that ClC-1 function is controlled by multiple cellular signals during muscle activity. Thus, onset of muscle activity triggers ClC-1 inhibition via protein kinase C, intracellular acidosis, and lactate ions. This inhibition is important for preserving excitability of working muscle in the face of activity-induced elevation of extracellular K+ and accumulating inactivation of voltage-gated sodium channels. Furthermore, during prolonged activity, a marked ClC-1 activation can develop that compromises muscle excitability. Data from ClC-1 expression systems suggest that this ClC-1 activation may arise from loss of regulation by adenosine nucleotides and/or oxidation. The present review summarizes the current knowledge of the physiological factors that control ClC-1 function in active muscle.

The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel

“…We cannot exclude that the mutation may affect the channel regulation by intracellular metabolites. Indeed, previous studies have shown that the C-terminal cytoplasmic domain is sensitive to a range of modulators (Pedersen, Riisager, de Paoli, Chen, & Nielsen, 2016), including nucleotides, such as ATP and NAD+, or regulatory proteins such as PKC (Bennetts et al, 2005(Bennetts et al, , 2012Hsiao et al, 2010;Tseng et al, 2011). The mutation p.Leu861Pro falls within the putative ATP binding site in CBS2, including residues Glu865 and His847 and Leu848 (Bennetts et al, 2012;Tseng et al, 2011).…”

The chloride anion as a signalling effector

“…The aim of this review is to update knowledge regarding the specific functions of the chloride anion as a signalling effector, acting as a modulator of other signals, as a specific ligand for certain enzymes and proteins, or as a second messenger for receptors and channels. We will not review the specific roles of Cl − channels in cell signalling, physiology and pathophysiology, which have been extensively reviewed elsewhere (Alvarez-Leefmans & Delpire, 2010;Hartzell, 2010;Sala-Rabanal et al, 2015;Kunzelmann, 2016;Kunzelmann et al, 2016;Pedersen et al, 2016;Sabirov et al, 2016;Wanitchakool et al, 2016).…”

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

“…Despite the presence of low-level expression in some other tissues, the ClC-1 channel is virtually exclusively expressed in skeletal muscles (52,53). While multiple types of Cl − channels exist in skeletal muscles, the ClC-1 channel is the most abundant (54)(55)(56). In most adult mammalian cells, the extracellular Cl − concentration is significantly higher than its intracellular counterpart, leading to a negative Cl − equilibrium potential (57).…”

“…In addition to the sarcolemma, a significant Cl − conductance is also present in the transverse-tubule system of skeletal muscle (59,(62)(63)(64). Although the precise subcellular localization pattern of ClC-1 in skeletal muscles remains contentious (56,(65)(66)(67)(68)(69)(70), it is likely that ClC-1 is important for maintaining an effective Cl − homeostasis system in both the sarcolemma and the transversetubule system. Taken together, activation of the ClC-1 channel is crucial for ensuring electrical stability of skeletal muscles by resetting membrane excitability after firing an action potential.…”