Activation of ATP-sensitive potassium currents in guinea-pig gall-bladder smooth muscle by the neuropeptide CGRP.

1. The actions of a neuroactive peptide, calcitonin gene-related peptide (CGRP), and the ATP-sensitive potassium (K+ATP) channel activator lemakalim on guinea-pig gall-bladder smooth muscle cells were investigated using intracellular recording from intact preparations and whole-cell patch clamp recording from acutely dissociated myocytes. 2. CGRP and lemakalim caused a glibenclamide-sensitive hyperpolarization of the plasma membrane of intact cells with an associated suppression of spontaneous action potentials. 3. In isolated smooth muscle cells, CGRP (10 nM) and lemakalim (10 microM) activated currents that were glibenclamide sensitive, voltage independent and potassium selective. 4. External TEA+ at 1.0 and 10.0 mM inhibited glibenclamide-sensitive, CGRP-activated currents by 3.8 and 66.5%, respectively. 5. Increases in the intracellular ATP concentration from 0.1 to 5.0 mM reduced the glibenclamide-sensitive potassium current in the presence of CGRP (10 nM) or lemakalim (10 microM) by > 60%. The increase in the intracellular ATP also reduced the steady-state glibenclamide-sensitive current by > 80%. 6. These findings indicate that CGRP activates K+ATP channels to hyperpolarize the membrane of gall-bladder smooth muscle cells. This hyperpolarization may be an important mechanism underlying the relaxant effects of CGRP on the gall-bladder.