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J. Biol. Chem., Vol. 277, Issue 41, 38373-38380, October 11, 2002

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G Protein-independent Activation of an Inward Na⁺ Current by Muscarinic Receptors in Mouse Pancreatic -Cells^*

Jean-François Rolland, Jean-Claude Henquin, and Patrick Gilon

From the Unité d'Endocrinologie et Métabolisme, University of Louvain, Faculty of Medicine, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium

Depolarization of pancreatic -cells is critical for stimulation of insulin secretion by acetylcholine but remains unexplained. Using voltage-clamped -cells, we identified a small inward current produced by acetylcholine, which was suppressed by atropine or external Na⁺ omission, but was not mimicked by nicotine, and was insensitive to nicotinic antagonists, tetrodotoxin, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DiDS), thapsigargin pretreatment, and external Ca²⁺ and K⁺ removal. This suggests that muscarinic receptor stimulation activates voltage-insensitive Na⁺ channels distinct from store-operated channels. No outward Na⁺ current was produced by acetylcholine when the electrochemical Na⁺ gradient was reversed, indicating that the channels are inward rectifiers. No outward K⁺ current occurred either, and the reversal potential of the current activated by acetylcholine in the presence of Na⁺ and K⁺ was close to that expected for a Na⁺-selective membrane, suggesting that the channels opened by acetylcholine are specific for Na⁺. Overnight pretreatment with pertussis toxin or the addition of guanosine 5'-O-(3-thiotriphosphate) (GTP--S) or guanosine-5'-O-(2-thiodiphosphate) (GDP--S) instead of GTP to the pipette solution did not alter this current, excluding involvement of G proteins. Injection of a current of a similar amplitude to that induced by acetylcholine elicited electrical activity in -cells perifused with a subthreshold glucose concentration. These results demonstrate that muscarinic receptor activation in pancreatic -cells triggers, by a G protein-independent mechanism, a selective Na⁺ current that explains the plasma membrane depolarization.

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