title: Protein kinase C theta (PKCθ) modulates the ClC-1 chloride channel activity and skeletal muscle phenotype: a biophysical and gene expression study in mouse models lacking the PKCθ.
abstract: In skeletal muscle, the resting chloride conductance (gCl), due to the ClC-1 chloride channel, controls the sarcolemma electrical stability. Indeed, loss-of-function mutations in ClC-1 gene are responsible of myotonia congenita. The ClC-1 channel can be phosphorylated and inactivated by protein kinases C (PKC), but the relative contribution of each PKC isoforms is unknown. Here, we investigated on the role of PKCθ in the regulation of ClC-1 channel expression and activity in fast- and slow-twitch muscles of mouse models lacking PKCθ. Electrophysiological studies showed an increase of gCl in the PKCθ-null mice with respect to wild type. Muscle excitability was reduced accordingly. However, the expression of the ClC-1 channel, evaluated by qRT-PCR, was not modified in PKCθ-null muscles suggesting that PKCθ affects the ClC-1 activity. Pharmacological studies demonstrated that although PKCθ appreciably modulates gCl, other isoforms are still active and concur to this role. The modification of gCl in PKCθ-null muscles has caused adaptation of the expression of phenotype-specific genes, such as calcineurin and myocyte enhancer factor-2, supporting the role of PKCθ also in the settings of muscle phenotype. Importantly, the lack of PKCθ has prevented the aging-related reduction of gCl, suggesting that its modulation may represent a new strategy to contrast the aging process.
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, 70125, Bari, Italy.
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Camerino
authors.forename: Marina
authors.initials: M
authors.lastname: Bouchè
authors.forename: Michela
authors.initials: M
authors.lastname: De Bellis
authors.forename: Maria
authors.initials: M
authors.lastname: Cannone
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.forename: Kejla
authors.initials: K
authors.lastname: Musaraj
authors.forename: Rossella
authors.initials: R
authors.lastname: Romano
authors.forename: Piera
authors.initials: P
authors.lastname: Smeriglio
authors.forename: Luca
authors.initials: L
authors.lastname: Madaro
authors.forename: Arcangela
authors.initials: A
authors.lastname: Giustino
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
authors.forename: Sabata
authors.initials: S
authors.lastname: Pierno
mesh_terms: D000200:Action Potentials; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D002712:Chlorides; D007527:Isoenzymes; D064326:MEF2 Transcription Factors; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D019703:Calcineurin