PubMed · 7798949
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D H Small. 1995. A function for butyrylcholinesterase?. https://doi.org/10.1046/j.1471-4159.1995.64010466.x
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Mutation of the highly conserved leucine residue (Leu-247) converts 5-hydroxytryptamine (5HT) from an antagonist into an agonist of neuronal homomeric alpha7 nicotinic acetylcholine receptor expressed in Xenopus oocytes. We show here that acetylcholine (AcCho) activates two classes of single channels with conductances of 44 pS and 58 pS, similar to those activated by 5HT. However, the mean open time of AcCho-gated ion channels (11 ms) is briefer than that of 5HT-gated ion channels (18 ms). Furthermore, whereas the open time of AcCho channels lengthens with hyperpolarization, that of 5HT channels is decreased. In voltage-clamped oocytes, the apparent affinity of the alpha7 mutant receptor for 5HT is not modified by the presence of dihydro-beta-erythroidine, which acts on the AcCho binding site in a competitive manner. This indicates a noncompetitive action of 5HT on nicotinic acetylcholine receptors. Considered together, our findings show that AcCho gates alpha7 mutant channels with similar conductance but with different kinetic profile than the channels gated by 5HT, suggesting that the two agonists act on different docking sites. These results will help to understand the crosstalk between cholinergic and serotonergic systems in the central nervous system.
Hypersecretion of insulin from the pancreas is among the earliest detectable metabolic alterations in some genetically obese animals including the ob/ob mouse and in some obesity-prone humans. Since the primary cause of obesity in the ob/ob mouse is a lack of leptin due to a mutation in the ob gene, we tested the hypothesis that leptin targets a regulatory pathway in pancreatic islets to prevent hypersecretion of insulin. Insulin secretion is regulated by changes in blood glucose, as well as by peptides from the gastrointestinal tract and neurotransmitters that activate the pancreatic islet adenylyl cyclase (e.g., glucagon-like peptide-1) and phospholipase C (PLC) (e.g., acetylcholine) signaling pathways to further potentiate glucose-induced insulin secretion. Effects of leptin on each of these regulatory pathways were thus examined. Leptin did not influence glucose or glucagon-like peptide-1-induced insulin secretion from islets of either ob/ob or lean mice, consistent with earlier findings that these regulatory pathways do not contribute to the early-onset hypersecretion of insulin from islets of ob/ob mice. However, leptin did constrain the enhanced PLC- mediated insulin secretion characteristic of islets from ob/ob mice, without influencing release from islets of lean mice. A specific enhancement in PLC-mediated insulin secretion is the earliest reported developmental alteration in insulin secretion from islets of ob/ob mice, and thus a logical target for leptin action. This action of leptin on PLC-mediated insulin secretion was dose-dependent, rapid-onset (i.e., within 3 min), and reversible. Leptin was equally effective in constraining the enhanced insulin release from islets of ob/ob mice caused by protein kinase C (PKC) activation, a downstream mediator of the PLC signal pathway. One function of leptin in control of body composition is thus to target a PKC-regulated component of the PLC-PKC signaling system within islets to prevent hypersecretion of insulin.
Muscarinic m2 and m4 receptors couple preferentially to inhibition of adenylyl cyclase, whereas m1, m3, and m5 receptors couple preferentially to activation of phospholipase C-beta and in some cells to stimulation of cAMP. Smooth muscle cells were shown to express adenylyl cyclases types V and/or VI. Acetylcholine (ACh) stimulated the binding of [35S]GTPgammaS.Galpha complexes in smooth muscle membranes to Galphaq/11 and Galphai3 antibody. Binding to Galphaq/11 antibody was inhibited by the m3 receptor antagonist, 4-DAMP, and binding to Galphai3 antibody was inhibited by the m2 receptor antagonist, N,N'-bis[6[[(2-methoxyphenyl)methyl]amino]hexyl]-1,8-octanediamine tetrahydrochloride (methoctramine). The decrease in basal cAMP (35 +/- 5%) induced by ACh in dispersed muscle cells was accentuated by 4-DAMP or Gbeta antibody (55 +/- 8 to 63 +/- 6%). In contrast, methoctramine, pertussis toxin (PTx), or Galphai3 antibody converted the decrease in cAMP to increase above basal level (+28 +/- 5 to +32 +/- 6%); the increase in cAMP was abolished by 4-DAMP or Gbeta antibody. In muscle cells where only m3 receptors were preserved by selective receptor protection, ACh caused only an increase in cAMP that was abolished by 4-DAMP. Conversely, in muscle cells where only m2 receptors were preserved, ACh caused an accentuated decrease in cAMP that was abolished by methoctramine or PTx. In conclusion, m2 receptors in smooth muscle couple to inhibition of adenylyl cyclases V/VI via Galphai3, and m3 receptors couple to activation of the enzymes via Gbetagammaq/11.