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

Thomas Holm Pedersen, Anders Riisager, Frank Vincenzo de Paoli, Tsung-Yu Chen, Ole Bækgaard Nielsen

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)291-308
Number of pages18
JournalJournal of General Physiology
Volume147
Issue number4
DOIs
StatePublished - 2016

Fingerprint

Ion Channels
Skeletal Muscle
Muscles
Membranes
Myotonia Congenita
Myotonia
Ions
Voltage-Gated Sodium Channels
Reptiles
Active Biological Transport
Skeletal Muscle Fibers
Amphibians
Acidosis
Membrane Potentials
Adenosine
Protein Kinase C
Action Potentials
Birds
Mammals
Permeability

ASJC Scopus subject areas

  • Physiology

Cite this

Role of physiological ClC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle. / Pedersen, Thomas Holm; Riisager, Anders; de Paoli, Frank Vincenzo; Chen, Tsung-Yu; Nielsen, Ole Bækgaard.

In: Journal of General Physiology, Vol. 147, No. 4, 2016, p. 291-308.

Research output: Contribution to journalArticle

Pedersen, Thomas Holm ; Riisager, Anders ; de Paoli, Frank Vincenzo ; Chen, Tsung-Yu ; Nielsen, Ole Bækgaard. / Role of physiological ClC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle. In: Journal of General Physiology. 2016 ; Vol. 147, No. 4. pp. 291-308.
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