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

• Published in: Pflügers Archiv Vol. 466; no. 12; pp. 2215 - 2228
• Main Authors: Camerino, Giulia Maria, Bouchè, Marina, De Bellis, Michela, Cannone, Maria, Liantonio, Antonella, Musaraj, Kejla, Romano, Rossella, Smeriglio, Piera, Madaro, Luca, Giustino, Arcangela, De Luca, Annamaria, Desaphy, Jean-François, Camerino, Diana Conte, Pierno, Sabata
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2014; Springer Verlag
• Subjects: Action Potentials; Animal biology; Animals; Biochemistry, Molecular Biology; Biomedical and Life Sciences; Biomedicine; Calcineurin - genetics; Calcineurin - metabolism; Cell Biology; Chloride Channels - metabolism; Chlorides - metabolism; Human health and pathology; Human Physiology; Ion Channels; Isoenzymes - genetics; Isoenzymes - metabolism; Life Sciences; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; Molecular biology; Molecular Medicine; Muscle Fibers, Fast-Twitch - metabolism; Muscle Fibers, Fast-Twitch - physiology; Muscle Fibers, Slow-Twitch - metabolism; Muscle Fibers, Slow-Twitch - physiology; Neurosciences; Phenotype; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinase C-theta; Receptors; Receptors and Transporters; Rhumatology and musculoskeletal system; ClC-1 chloride channel; Phenotype; PKCθ; Electrophysiology; Aging; Gene expression; Skeletal muscle
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-014-1495-1

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.