Muscarinic regulation of ether-a-go-go-related gene K+ currents in interstitial cells of Cajal

The interstitial cells of Cajal (ICC) of the myenteric plexus generate a set of currents that evoke a pacemaker potential that sets the initial conditions for the contraction frequency and duration of the electrically coupled intestinal musculature. The synapse-like contacts between ICC and myenteric motor nerves highlight the potential role of the enteric nervous system in regulating the pacemaking currents in ICC. The objective of the present study was to investigate muscarinic regulation of the ether-a-go-go-related gene (ERG) K+ current. Immunoreactivity of the M-3 receptor (M3R) but not the M-2 receptor was detected on murine jejunal ICC-Auerbach's plexus (ICC-AP). The muscarinic agonist bethanechol reduced hyperpolarization-evoked peak ERG currents at -100 mV by 23 +/- 1% and increased both fast and slow time constants of deactivation, resulting in increased steady-state currents between -55 and -35 mV. Bethanechol also increased depolarization-evoked steady-state currents by 59 +/- 10% at -40 mV, whereas currents were decreased at potentials positive to 0 mV. The half-maximal voltage of activation was shifted 11.9 mV leftward. Interestingly, the time constant of activation increased only at -40 mV. Atropine prevented and 2 mu M E4031 [1-[2-(6-methyl2-pyridyl)-ethyl-4-(methylsulfonylaminobenzoyl)piperidine] inhibited bethanechol-affected currents. The effect of bethanechol was mimicked by protein kinase C (PKC) activation and diminished by PKC inhibition. Our results indicate that the ERG K+ channel in ICC is affected by stimulation of muscarinic receptors, probably the M 3 R, via a PKC-dependent mechanism. Modulation of the ERG K+ current in ICC-AP will affect the kinetics of pacemaking in the intestinal musculature.