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1 Laboratoire de Physiologie des Eléments Excitables, UMR CNRS 5123, UCB-Lyon 1, 69622 Villeurbanne Cedex, France2 Department of Physiology, University of Wisconsin, Madison, WI 53706, USA
Caveolae and transverse (T-) tubules are membrane structures enriched in cholesterol and glycosphingolipids. They play an important role in receptor signalling and myogenesis. The T-system is also highly enriched in dihydropyridine receptors (DHPRs), which control excitation–contraction (E–C) coupling. Recent results have shown that a depletion of membrane cholesterol alters caveolae and T-tubules, yet detailed functional studies of DHPR expression are lacking. Here we studied electrophysiological and morphological effects of methyl-ß-cyclodextrin (MßCD), a cholesterol-sequestering drug, on freshly isolated fetal skeletal muscle cells. Exposure of fetal myofibres to 1–3 mM MßCD for 1 h at 37°C led to a significant reduction in caveolae and T-tubule areas and to a decrease in cell membrane electrical capacitance. In whole-cell voltage-clamp experiments, the L-type Ca2+ current amplitude was significantly reduced, and its voltage dependence was shifted 
15 mV towards more positive potentials. Activation and inactivation kinetics were slower in treated cells than in control cells and stimulation by a saturating concentration of Bay K 8644 was enhanced. In addition, intramembrane charge movement and Ca2+ transients evoked by a depolarization were reduced without a shift of the midpoint, indicating a weakening of E–C coupling. In contrast, T-type Ca2+ current was not affected by MßCD treatment. Most of the L-type Ca2+ conductance reduction and E–C coupling weakening could be explained by a decrease of the number of DHPRs due to the disruption of caveolae and T-tubules. However, the effects on L-type channel gating kinetics suggest that membrane cholesterol content modulates DHPR function. Moreover, the significant shift of the voltage dependence of L-type current without any change in the voltage dependence of charge movement and Ca2+ transients suggests that cholesterol differentially regulates the two functions of the DHPR.
(Received 17 September 2003;
accepted after revision 5 January 2004;
first published online 14 January 2004)
Corresponding author C. Strube: LNPC, CNRS UMR 6150, Faculté Médecine Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20, France. Email: strube.c{at}jean-roche.univ-mrs.fr
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