Receptor signaling mechanisms underlying muscarinic agonist‐evoked contraction in guinea‐pig ileal longitudinal smooth muscle

Abstract

1 In guinea-pig ileal longitudinal muscle, muscarinic partial agonists, 4-(N-[3-chlorophenyl]-carbomoyloxy)-2-butynyl-trimethylammonium (McN-A343) and pilocarpine, each produced parallel increases in tension and cytosolic Ca 2+ concentration ([Ca 2+ ]c) with a higher EC 50 than that of the full agonist carbachol. The maximum response of [Ca 2+ ]c or tension was not much different among the three agonists. The Ca 2+ channel blocker nicardipine markedly inhibited the effects of all three agonists 2 The contractile response to any agonist was antagonized in a competitive manner by M 2 receptor selective antagonists (N,benzodiazepine-6-one), and the apparent order of M 2 antagonist sensitivity was McN-A3434pilo-carpine4carbachol. M 3 receptor selective antagonists, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide and darifenacin, both severely depressed the maximum response for McN-A343, while darifenacin had a similar action in the case of pilocarpine. Both M 3 antagonists behaved in a competitive manner in the case of the carbachol response. -releasing action of pilocarpine was very weak compared with that of carbachol. All three agonists were capable of increasing Ca 2+ sensitivity of the contractile proteins. 4 McN-A343 rarely produced membrane depolarization, but always accelerated electrical spike discharge. Pilocarpine effect was more often accompanied by membrane depolarization, as was usually seen using carbachol. 5 The results suggest that muscarinic agonist-evoked contractions result primarily from the integration of Ca 2+ entry associated with the increased spike discharge and myofilaments Ca 2+ sensitization, and that Ca 2+ store release may contribute to the contraction indirectly via potentiation of the electrical membrane responses. They may also support the idea that an interaction of M 2 and M 3 receptors plays a crucial role in mediating the contraction response.

Acupuncture at heterotopic acupoints facilitates distal colonic motility via activating M3 receptors and somatic afferent C‐fibers in normal, constipated, or diarrhoeic rats

“…Acetylcholine activates muscarinic receptors on the smooth muscle cell surface directly or indirectly, thus triggering various intracellular signaling pathways, which eventually lead to smooth muscle contraction. [27][28][29] In this study, we examined the effect of acupuncture at heterotopic acupoints on distal colonic motility in normal rats, constipated or diarrhoeic rats. We tested the hypothesis that the effects of acupuncture on distal colonic motility are associated with the distribution of cholinergic muscarinic receptors, and that activation of Ad-and/or C-fibers may be required for increased colonic motility by acupuncture at heterotopic acupoints.…”

Phospholipase C Involvement in Activation of the Muscarinic Receptor-Operated Cationic Current in Guinea Pig Ileal Smooth Muscle Cells

“…The evoked I cat , via causing membrane depolarization, leads to sustained increases in the open probability of voltage-gated Ca 2+ channels and/ or to increased discharges of Ca 2+ action potentials, providing substantial Ca 2+ influx for contraction (3,4). In various gastrointestinal smooth muscles, two major subtypes of the muscarinic receptor, M2 and M3, are found.…”

Identification of GIRK2-4 subunits in human esophageal smooth muscle cells

“…Third, M2 receptor also inhibits potassium channels and opens non-specific cation channels to induce contraction (30). Under physiological ionic conditions, the muscarinic receptor-mediated current is carried with a reversal potential between -10 and 0 mV, whereby depolarization is produced; thus, the discharge of action and slow-wave potentials initiates or accelerates unless the depolarization is extremely strong (31,32). Previous studies have shown that ACh activates and modulates the activity of GIRK channels in esophageal SMCs (33,34).…”