RETRACTED: Functional characterization of a nonclassical nicotine receptor associated with inositolphospholipid breakdown and mobilization of intracellular calcium pools.

Abstract

Classical nicotinic receptors are neurotransmitter-gated channels that, upon activation by acetylcholine, induce the opening of an intrinsic cationic channel. We have recently observed that, in frog pituitary melanotrophs, nicotine stimulates alpha-melanocyte-stimulating hormone (alpha-MSH) release through a noncholinergic mechanism. In the study reported here, we investigated the intracellular events that mediate the response of frog melanotrophs to nicotine. Nicotine was capable of stimulating alpha-MSH release in the absence of Ca2+ and/or Na+ in the extracellular medium. A short pulse of nicotine induced a rapid and transient increase of cytosolic free Ca2+ concentration ([Ca2+]i). The effect of nicotine on Ca2+ mobilization was not affected in the absence of Na+ and Ca2+ in the extracellular medium, indicating that the nicotine-evoked increase in [Ca2+]i did not result from Na+ or Ca2+ influx. Nicotine induced both an increase in inositol trisphosphate and a reduction in phosphaditylinositol bisphosphate concentrations but did not affect cAMP production. The present results indicate that nicotine-induced stimulation of alpha-MSH release in frog melanotrophs can be explained by activation of inositolphospholipid breakdown and mobilization of inositol triphosphate-dependent intracellular Ca2+ pools. These data provide evidence for the existence of an unusual type of noncholinergic nicotine receptor positively coupled to phospholipase C.

A Functional Role for Nicotine in Bcl2 Phosphorylation and Suppression of Apoptosis

“…Nicotine has been reported to induce PLC activation through a nonclassical nicotine receptor signal pathway (7). Activated PLC hydrolyzes phosphatidylinositol bisphosphate to generate both phosphatidylinositol 1,4,5-trisphosphate and diacylglycerol second messengers (7,9). Phosphatidylinositol 1,4,5-trisphosphate increases cytosolic Ca 2ϩ concentration by releasing Ca 2ϩ from the endoplasmic reticulum, which may facilitate activation of classical PKCs (9).…”

“…Classical nicotine signaling occurs through the nicotinic acetylcholine receptor (nAChR) 1 superfamily, which consists of ␣, ␤, ␥, ⑀, and ␦ subunits (7). These nAChRs are transmembrane cationic channels that are activated on cholinergic stimulation (7). The nonclassical nicotine receptor pathway is mediated through a noncholinergic metabotropic receptor, which is not sensitive to acetylcholine (7,10,11).…”

“…These nAChRs are transmembrane cationic channels that are activated on cholinergic stimulation (7). The nonclassical nicotine receptor pathway is mediated through a noncholinergic metabotropic receptor, which is not sensitive to acetylcholine (7,10,11). The nonclassical receptor type belongs to the G protein-linked receptor superfamily, which contains seven hydrophobic transmembrane domains and is positively coupled to PLC (7).…”

“…Nicotine signaling can occur as a result of activation of either the classical and/or nonclassical nicotine receptor pathways (6 -9). Classical nicotine signaling occurs through the nicotinic acetylcholine receptor (nAChR) 1 superfamily, which consists of ␣, ␤, ␥, ⑀, and ␦ subunits (7). These nAChRs are transmembrane cationic channels that are activated on cholinergic stimulation (7).…”

“…The nonclassical nicotine receptor pathway is mediated through a noncholinergic metabotropic receptor, which is not sensitive to acetylcholine (7,10,11). The nonclassical receptor type belongs to the G protein-linked receptor superfamily, which contains seven hydrophobic transmembrane domains and is positively coupled to PLC (7). The hydrolysis of a minor membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (12), through the direct action of phospholipase C is one of the earliest key events in the regulation of various cell functions by extracellular signaling molecules (12)(13)(14)(15).…”