title: Control of intracellular calcium in the presence of nitric oxide donors in isolated skeletal muscle fibres from mouse.
abstract: In skeletal muscle, nitric oxide (NO) is commonly referred to as a modulator of the activity of the ryanodine receptor (RyR) calcium release channel. However the reported effects of NO on isolated sarcoplasmic reticulum (SR) preparations and single ryanodine receptor (RyR) activity are diverse, and how NO affects SR calcium release and intracellular calcium homeostasis under physiological conditions remains poorly documented and hardly predictable. Here, we studied the effects of NO donors on membrane current and intracellular [Ca(2+)] in single skeletal muscle fibres from mouse, under voltage-clamp conditions. When fibres were chronically exposed to millimolar levels of sodium nitroprusside (SNP) and challenged by short membrane depolarizations, there was a progressive increase in the resting [Ca(2+)] level. This effect was use-dependent with the slope of rise in resting [Ca(2+)] being increased two-fold when the depolarizing pulse level was raised from -20 to +10 mV. Analysis of the decay of the [Ca(2+)] transients suggested that cytoplasmic Ca(2+) removal processes were largely unaffected by the presence of SNP. Also the functional properties of the dihydropyridine receptor were very similar under control conditions and in the presence of SNP. The resting [Ca(2+)] elevation due to SNP was accompanied by a depression of the peak calcium release elicited by pulses to +10 mV. The effects of SNP could be reproduced by the chemically distinct NO donor NOC-12. They could be reversed upon exposure of the fibres to the thiol reducing agent dithiothreitol. Results suggest that large levels of NO produce a redox-sensitive continuous leak of Ca(2+) from the SR, through a limited number of release channels that do not close once they are activated by membrane depolarization. This SR Ca(2+) leak and the resulting increase in resting [Ca(2+)] may be important in mediating the effects of excess NO on voltage-activated calcium release.
authors.affiliation: Physiologie Intégrative Cellulaire et Moléculaire, Université Claude Bernard - Lyon 1, UMR CNRS 5123, Bât. Raphael Dubois, 43 boulevard du 11 novembre 1918, F 69622 Villeurbanne Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pouvreau
authors.forename: Bruno
authors.initials: B
authors.lastname: Allard
authors.forename: Christine
authors.initials: C
authors.lastname: Berthier
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacquemond
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*
chemical_list: D020030:Nitric Oxide Donors; D002118:Calcium