title: 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.
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark thp@biomed.au.dk.
authors.forename: Thomas Holm
authors.initials: TH
authors.lastname: Pedersen
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Riisager
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Frank Vincenzo
authors.initials: FV
authors.lastname: de Paoli
authors.affiliation: Center for Neuroscience and Department of Neurology, University of California, Davis, Davis, CA 95618 Center for Neuroscience and Department of Neurology, University of California, Davis, Davis, CA 95618.
authors.forename: Tsung-Yu
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Ole Bækgaard
authors.initials: OB
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D009224:Myotonia Congenita / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018118:Chloride Channels