QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.109322v1 319/3/1112    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McKay, C. M. Articles by Huizinga, J. D. Search for Related Content PubMed PubMed Citation Articles by McKay, C. M. Articles by Huizinga, J. D.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Muscarinic Regulation of Ether-a-go-go-Related Gene K⁺ Currents in Interstitial Cells of Cajal

Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada

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 M₃ receptor (M₃R) but not the M₂ 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 µM E4031 [1-[2-(6-methyl-2-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 M₃R, via a PKC-dependent mechanism. Modulation of the ERG K⁺ current in ICC-AP will affect the kinetics of pacemaking in the intestinal musculature.

Address correspondence to: Dr. Jan D. Huizinga, McMaster University, HSC-3N5C, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. E-mail: huizinga{at}mcmaster.ca