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J Physiol
2016 Jun 15;59412:3391-406. doi: 10.1113/JP271556.
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Protein kinase C-dependent regulation of ClC-1 channels in active human muscle and its effect on fast and slow gating.
Riisager A
,
de Paoli FV
,
Yu WP
,
Pedersen TH
,
Chen TY
,
Nielsen OB
.
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KEY POINTS: Regulation of ion channel function during repeated firing of action potentials is commonly observed in excitable cells. Recently it was shown that muscle activity is associated with rapid, protein kinase C (PKC)-dependent ClC-1 Cl(-) channel inhibition in rodent muscle. While this PKC-dependent ClC-1 inhibition during muscle activity was shown to be important for the maintenance of contractile endurance in rat muscle it is unknown whether a similar regulation exists in human muscle. Also, the molecular mechanisms underlying the observed PKC-dependent ClC-1 inhibition are unclear. Here we present the first demonstration of ClC-1 inhibition in active human muscle fibres, and we determine the changes in ClC-1 gating that underlie the PKC-dependent ClC-1 inhibition in active muscle using human ClC-1 expressed in Xenopus oocytes. This activity-induced ClC-1 inhibition is suggested to represent a mechanism by which human muscle fibres maintain their excitability during sustained activity.
ABSTRACT: Repeated firing of action potentials (APs) is known to trigger rapid, protein kinase C (PKC)-dependent inhibition of ClC-1 Cl(-) ion channels in rodent muscle and this inhibition is important for contractile endurance. It is currently unknown whether similar regulation exists in human muscle, and the molecular mechanisms underlying PKC-dependent ClC-1 inhibition are unclear. This study first determined whether PKC-dependent ClC-1 inhibition exists in active human muscle, and second, it clarified how PKC alters the gating of human ClC-1 expressed in Xenopus oocytes. In human abdominal and intercostal muscles, repeated AP firing was associated with 30-60% reduction of ClC-1 function, which could be completely prevented by PKC inhibition (1 μm GF109203X). The role of the PKC-dependent ClC-1 inhibition was evaluated from rheobase currents before and after firing 1000 APs: while rheobase current was well maintained after activity under control conditions it rose dramatically if PKC-dependent ClC-1 inhibition had been prevented with the inhibitor. This demonstrates that the ClC-1 inhibition is important for maintenance of excitability in active human muscle fibres. Oocyte experiments showed that PKC activation lowered the overall open probability of ClC-1 in the voltage range relevant for AP initiation in muscle fibres. More detailed analysis of this reduction showed that PKC mostly affected the slow gate of ClC-1. Indeed, there was no effect of PKC activation in C277S mutated ClC-1 in which the slow gate is effectively locked open. It is concluded that regulation of excitability of active human muscle fibres relies on PKC-dependent ClC-1 inhibition via a gating mechanism.
Accardi,
Fast and slow gating relaxations in the muscle chloride channel CLC-1.
2000, Pubmed,
Xenbase
Accardi,
Fast and slow gating relaxations in the muscle chloride channel CLC-1.
2000,
Pubmed
,
Xenbase
Accardi,
Drastic reduction of the slow gate of human muscle chloride channel (ClC-1) by mutation C277S.
2001,
Pubmed
,
Xenbase
Bennetts,
Cytoplasmic ATP-sensing domains regulate gating of skeletal muscle ClC-1 chloride channels.
2005,
Pubmed
Bennetts,
Molecular determinants of common gating of a ClC chloride channel.
2013,
Pubmed
Brinkmeier,
Activators of protein kinase C induce myotonia by lowering chloride conductance in muscle.
1987,
Pubmed
Bryant,
Chloride conductance in normal and myotonic muscle fibres and the action of monocarboxylic aromatic acids.
1971,
Pubmed
Bryant,
Chloride channel regulation in the skeletal muscle of normal and myotonic goats.
1991,
Pubmed
Bykova,
Large movement in the C terminus of CLC-0 chloride channel during slow gating.
2006,
Pubmed
Chen,
Role of phosphorylation and physiological state in the regulation of the muscular chloride channel ClC-1: a voltage-clamp study on isolated M. interosseus fibers.
1999,
Pubmed
Cozzoli,
Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase.
2014,
Pubmed
de Paoli,
Relationship between membrane Cl- conductance and contractile endurance in isolated rat muscles.
2013,
Pubmed
Duffield,
Involvement of helices at the dimer interface in ClC-1 common gating.
2003,
Pubmed
Dutzler,
X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity.
2002,
Pubmed
Estévez,
Functional and structural conservation of CBS domains from CLC chloride channels.
2004,
Pubmed
,
Xenbase
Feng,
Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle.
2010,
Pubmed
Fink,
An evaluation of the membrane constants and the potassium conductance in metabolically exhausted muscle fibres.
1976,
Pubmed
Hebeisen,
Carboxy-terminal truncations modify the outer pore vestibule of muscle chloride channels.
2005,
Pubmed
Hodgkin,
The effect of diameter on the electrical constants of frog skeletal muscle fibres.
1972,
Pubmed
HODGKIN,
The electrical constants of a crustacean nerve fibre.
1946,
Pubmed
Hsiao,
Functional study of CLC-1 mutants expressed in Xenopus oocytes reveals that a C-terminal region Thr891-Ser892-Thr893 is responsible for the effects of protein kinase C activator.
2010,
Pubmed
,
Xenbase
Jentsch,
CLC chloride channels and transporters: from genes to protein structure, pathology and physiology.
2008,
Pubmed
Koch,
The skeletal muscle chloride channel in dominant and recessive human myotonia.
1992,
Pubmed
Kwieciński,
The resting membrane parameters of human intercostal muscle at low, normal, and high extracellular potassium.
1984,
Pubmed
Lipicky,
Cable parameters, sodium, potassium, chloride, and water content, and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita.
1971,
Pubmed
Ma,
Movement of hClC-1 C-termini during common gating and limits on their cytoplasmic location.
2011,
Pubmed
McComas,
The electrical properties of muscle fiber membranes in dystrophia myotonica and myotonia congenita.
1968,
Pubmed
Miller,
ClC chloride channels viewed through a transporter lens.
2006,
Pubmed
Novak,
Sodium channel slow inactivation as a therapeutic target for myotonia congenita.
2015,
Pubmed
Palade,
Characteristics of the chloride conductance in muscle fibers of the rat diaphragm.
1977,
Pubmed
Pedersen,
Increased excitability of acidified skeletal muscle: role of chloride conductance.
2005,
Pubmed
Pedersen,
Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers.
2009,
Pubmed
Pedersen,
Comparison of regulated passive membrane conductance in action potential-firing fast- and slow-twitch muscle.
2009,
Pubmed
Pierno,
Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor.
2003,
Pubmed
Pierno,
Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression.
2009,
Pubmed
Pusch,
Myotonia caused by mutations in the muscle chloride channel gene CLCN1.
2002,
Pubmed
Riisager,
Determination of cable parameters in skeletal muscle fibres during repetitive firing of action potentials.
2014,
Pubmed
Rosenbohm,
Regulation of the human skeletal muscle chloride channel hClC-1 by protein kinase C.
1999,
Pubmed
Saviane,
The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia.
1999,
Pubmed
,
Xenbase
Sejersted,
Dynamics and consequences of potassium shifts in skeletal muscle and heart during exercise.
2000,
Pubmed
Skov,
Extracellular magnesium and calcium reduce myotonia in isolated ClC-1 chloride channel-inhibited human muscle.
2015,
Pubmed
Steinmeyer,
Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel.
1991,
Pubmed
,
Xenbase
Toullec,
The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.
1991,
Pubmed
Tricarico,
Modulation of rat skeletal muscle chloride channels by activators and inhibitors of protein kinase C.
1991,
Pubmed
Tseng,
Cytoplasmic ATP inhibition of CLC-1 is enhanced by low pH.
2007,
Pubmed
,
Xenbase
Wu,
Functional complementation of truncated human skeletal-muscle chloride channel (hClC-1) using carboxyl tail fragments.
2006,
Pubmed
,
Xenbase
Yamada,
Regulatory phosphorylation induces extracellular conformational changes in a CLC anion channel.
2013,
Pubmed
