Mechanosensitive ion channels in skeletal muscle: a link in the membrane pathology of muscular dystrophy.
1. Mechanosensitive (MS) channels are expressed abundantly in skeletal muscle at all stages of development. In recordings from membrane patches, MS channels are constitutively active at the resting potential. The channels are selective for cations and have a large single-channel conductance (approximately 25 pS in physiological saline) and a high Ca2+ permeability (relative permeability of Ca2+ to K+ (PCa/PK) = 7). 2. Mechanosensitive channel activity recorded from the surface of myotubes from dystrophic mdx mice was substantially greater than the activity recorded from wild-type myotubes. Increased channel activity in the mutant results from the induction in a subpopulation of channels of a novel MS gating mode characterized by markedly prolonged channel openings and inactivation in response to membrane stretch. 3. Membrane stretch or a strong depolarization causes an irreversible switch to the stretch-inactivated gating mode in mdx myotubes. A stretch-induced shift in MS channel gating mode may contribute to stretch-induced elevations in [Ca2+]i during the early stages of disease pathogenesis. 4. Abnormalities of MS channel behaviour are also detected in recordings from patches on flexor digitorum brevis fibres acutely isolated from mdx mice. Mechanosensitive channel opening probability is higher in mdx fibres at all developmental stages. In addition, channel numbers are persistently elevated during postnatal development, failing to undergo a normal process of downregulation during the first 3 postnatal weeks. 5. Two distinct mechanisms may contribute to elevations of [Ca2+]i in dystrophin-deficient skeletal muscle: (i) a membrane stress-dependent switch of MS channels into to a prolonged opening mode; and (ii) a loss of developmental downregulation leading to persistent MS channel expression during postnatal muscle development.
Lansman
Jeffry B
JB
Department of Cellular and Molecular Pharmacology, UCSF School of Medicine, San Francisco, California 94143-0450, USA. jeffl@itsa.ucsf.edu
Franco-Obregón
Alfredo
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D015640:Ion Channel Gating / Q000502:physiology*; D040542:Mechanotransduction, Cellular; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000503:physiopathology; D050052:TRPC Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; D002118:Calcium