Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 910, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174491
Keywords
Esophageal motility; Nicotinic acetylcholine receptor; Interstitial cells of Cajal; Smooth muscle; Lower esophageal sphincter
Categories
Funding
- Japan Society for the Promotion of Science KAKENHI [17K09351, 20K08334]
- Smoking Research Foundation [2017G026]
- Grants-in-Aid for Scientific Research [17K09351, 20K08334] Funding Source: KAKEN
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The interstitial cells of Cajal (ICCs) play a central role in DMPP-induced relaxation through membrane hyperpolarization via the activation of anoctamin-1. ATP may serve as a neurotransmitter for inhibitory enteric neurons that stimulate ICCs. ICCs act as the interface for neurotransmission of nicotinic acetylcholine receptor to induce LES relaxation.
The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 mu M tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 mu M carbenoxolone (a gap junction inhibitor), pretreatment with 100 mu M CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl--free solution. However, pretreatment with 100 mu M N degrees-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 mu M VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.
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