INHIBITION OF M-CURRENT IN CULTURED RAT SUPERIOR CERVICAL-GANGLIA BY LINOPIRDINE - MECHANISM OF ACTION STUDIES

The mechanism involved in the blockade of M-current by linopirdine was studied in cultured rat superior cervical sympathetic ganglia using w hole-cell patch clamp recording. The effects of modulators of intracel lular signal transduction pathways on muscarine-or linopirdine-induced inhibition of M-current were compared. Intracellular addition of GDP- beta-S (500 mu M) attenuated M-current block by muscarine (1 mu M) but not that of linopirdine (10 mu M). Intracellular dialysis of GTP-gamm a-S (100 mu M) enhanced and prolonged muscarine-induced inhibition of M-current but had no effect on the activity of linopirdine. Intracellu lar BAPTA (20 mM) also inhibited the effects of muscarine without affe cting those of linopirdine. Intracellular application of linopirdine h ad no effect on either basal M-current amplitude or the ability of lin opirdine to block M-current when administered extracellularly. These r esults indicate that M-current inhibition by linopirdine is unlikely t o be either G-protein-mediated or calcium-mediated or to involve an in tracellular site of action and are, therefore, consistent with a direc t block of the M-channel from its extracellular side. (C) 1998 Elsevie r Science Ltd. All rights reserved.