TREK-1 channels do not mediate nitrergic neurotransmission in circular smooth muscle from the lower oesophageal sphincter.
OBJECTIVE
The ionic mechanisms underlying nitrergic inhibitory junction potentials (IJPs) in gut smooth muscle remain a matter of debate. Recently, it has been reported that opening of TWIK-related K(+) channel 1 (TREK-1) K(+) channels contributes to the nitrergic IJP in colonic smooth muscle. We investigated the effects of TREK-1 channel blockers on nitrergic neurotransmission in mouse and opossum lower oesophageal sphincter (LOS) circular smooth muscle (CSM).


METHODS
The effects of TREK-1 channel blockers were characterized pharmacologically in murine and opossum gut smooth muscle using conventional intracellular and tension recordings.


RESULTS
In LOS, L-methionine depolarized the resting membrane potential (RMP) but did not inhibit the nitrergic IJP. Cumulative application of theophylline hyperpolarized the RMP and inhibited the nitrergic IJP concentration dependently. The induced membrane hyperpolarization was prevented by pre-application of caffeine, but not by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. 8-Br-cAMP significantly hyperpolarized membrane potential and increased the amplitude of the nitrergic IJP. In opossum LOS muscle strips, L-methionine increased resting tone but had no effect on nerve-mediated LOS relaxation. On the other hand, theophylline markedly inhibited tone. In CSM from mouse proximal colon, L-methionine caused modest inhibition of nitrergic IJPs.


CONCLUSIONS
TREK-1 channels were not involved in the nitrergic IJP in LOS CSM. Not only does L-methionine have no effect on the nitrergic IJP or LOS relaxation, but the effect of theophylline appears to be due to interruption of Ca(2+)-releasing pathways (i.e. caffeine-like effect) rather than via blockade of TREK-1 channels.
Zhang
Y
Y
Gastrointestinal Diseases Research Unit, Kingston General Hospital and Queen's University, Kingston, Ontario, Canada.
Miller
D V
DV
Paterson
W G
WG
D000818:Animals; D002118:Calcium / Q000502:physiology; D003106:Colon / Q000187:drug effects / Q000502:physiology; D049630:Esophageal Sphincter, Lower / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D008715:Methionine / Q000494:pharmacology; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009893:Opossums; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D009435:Synaptic Transmission; D013806:Theophylline / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D009569:Nitric Oxide; D008715:Methionine; D013806:Theophylline; D019001:Nitric Oxide Synthase; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester