Disease relevance of MUSCARINE

• Muscarine also raised [Ca2+]i, but it was less potent than nicotine, affecting only a subpopulation of ganglion cells, with an M1-like muscarinic receptor pharmacology [1].
• Bradykinin and muscarine induce Ca(2+)-dependent oscillations of membrane potential in rat glioma cells indicating a rhythmic Ca2+ release from internal stores: thapsigargin and 2,5-di(tert-butyl)-1, 4-benzohydroquinone deplete InsP3-sensitive Ca2+ stores in glioma and in neuroblastoma-glioma hybrid cells [2].
• Preincubation of frog NILs with pertussis toxin did not significantly affect the muscarine-induced stimulation of alphaMSH release [3].
• 2. Exposure to hypoxia, cyanide (CN), or muscarine facilitated CA secretion from dissociated chromaffin cells [4].
• Inhibition of N-type Ca2+ channel currents in human neuroblastoma (SH-SY5Y) cells by muscarine via stimulation of M3 receptors [5].

Psychiatry related information on MUSCARINE

• Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation [6].
• The muscarine cholinergic receptor blocker scopolamine (2 mg/kg, i. p.) substantially deteriorates short-term memory in passive avoidance training [7].

High impact information on MUSCARINE

• Phorbol ester facilitates 45Ca accumulation and catecholamine secretion by nicotine and excess K+ but not by muscarine in rat adrenal medulla [8].
• Long-term potentiation (LTP) of the mossy fiber-CA3 synapse was blocked by muscarine [9].
• Cerebral cortex samples from patients with Alzheimer's disease and from rats after experimental cholinergic denervation of the cerebral cortex exhibited reductions in the presynaptic marker choline acetyltransferase activity and in the number of M2 muscarine receptors, with no change in the number of M1 receptors [6].
• Here we show that in vitro gamma oscillations induced by muscarine require activation of M1 receptors on hippocampal CA3 pyramidal neurons and are absent in M1 receptor-deficient mice [10].
• Muscarine decreased M-channel activity by selectively reducing mode 2 M-channel gating through a diffusible second messenger [11].

Chemical compound and disease context of MUSCARINE

• Neither the nicotine- nor muscarine-induced increases of ganglion cell [Ca2+]i were blocked by the glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3-dione and aminophosphonopentanoic acid [1].
• Incubation with pertussis toxin did not alter the Ca2+ signals induced by muscarine, but did block depression of transmitter release induced by adenosine and prevented Ca2+ responses in PSCs induced by adenosine [12].
• The modulation of GABA-gated ion channel responses to GABA, pentobarbital and diazepam by muscarine was studied in freshly isolated rat dorsal root ganglion neurons using a whole-cell patch-clamp technique [13].
• Both actions of muscarine persisted when slices were pretreated with pertussis toxin or N-ethylmaleimide, which inactivate G-proteins coupled to M(2) and M(4) receptors while leaving G-proteins coupled to M(1), M(3) and M(5) receptors intact [14].
• 1. Calcium channel modulation by muscarine was investigated in cultured human neuroblastoma SH-SY5Y cells using the whole cell variant of the patch-clamp technique [15].

Biological context of MUSCARINE

• Genistein also inhibited the increases in Ser31 phosphorylation produced by phorbol dibutyrate, muscarine, and Ba2+ [16].
• Vasoactive intestinal polypeptide and muscarine mobilize intracellular Ca2+ through breakdown of phosphoinositides to induce catecholamine secretion. Role of IP3 in exocytosis [17].
• The data suggest that the muscarine receptor stimulated release of the alpha-synuclein oligomer from plasma membrane, and its subsequent association with the endocytotic vesicle fraction may have a role in muscarine receptor endocytosis [18].
• The sustained bronchoconstriction was reduced in mAChR2-/- bronchi, and, interestingly, the transient relaxation was absent; the bronchoconstriction in response to 10-8 M muscarine was increased by 158% in mAChR1-/- mice [19].
• Current-clamp recordings revealed a muscarine-induced shift in TC neuron activity from burst to tonic firing in both mouse genotypes [20].

Anatomical context of MUSCARINE

• METHODS: Muscarine, methacholine, and arecaidine propargyl ester were infused close-intra-arterially in the normal and inflamed ileum of conscious dogs [21].
• N-Ethylmaleimide (MalNEt) disclosed three differences between M2 muscarine receptors in membranes from the rat brainstem and M1 receptors in the hippocampus [22].
• [Ca2+]i elevations detected by BK channels during Ca2+ influx and muscarine-mediated release of Ca2+ from intracellular stores in rat chromaffin cells [23].
• Thus, SP decreases a conductance which appears similar to the muscarine-sensitive potassium conductance in sympathetic ganglion neurons (Brown, D. A., and P. R. Adams (1980) Nature 283: 673-676) [24].
• Muscarine hyperpolarizes a subpopulation of neurons by activating an M2 muscarinic receptor in rat nucleus raphe magnus in vitro [25].

Associations of MUSCARINE with other chemical compounds

• When a low dose of muscarine sufficient to inhibit IM, but not to elicit desensitization, was applied simultaneously with a desensitizing dose of SP, IM remained depressed and did not desensitize [26].
• Only atropine and the m3-m4-selective muscarinic antagonist 4-diphenylacetoxy-4-methyl-piperidine (4-DAMP) reduce the response to muscarine, strongly suggesting that the m4 receptor is crucial for PNMT mRNA activation [27].
• The production of [3H]inositol phosphates by VIP and muscarine occurred in calcium-free and EGTA medium [17].
• Neither k nor n is affected when: (a) [Bis-Q] is varied between 5 and 100 microM; (b) [carbachol] is varied between 1 and 50 microM; (c) carbachol is replaced by other agonists (muscarine, acetylcholine, or acetyl-beta-methylcholine); or (d) the voltage is varied between the normal resting potential and a depolarization of 80 mV [28].
• We now report that exposure of cultured cerebellar granule neurons, maintained under nondepolarizing conditions, to the muscarinic cholinergic receptor (mAchR) agonists carbachol and muscarine results in a concentration- and time-dependent inhibition of apoptosis [29].

Gene context of MUSCARINE

• The muscarine-elicited depression of ACh release in normal junctions was completely abolished by pertussis toxin or methoctramine pretreatment, but was not affected by muscarinic toxin MT-3, thus indicating the involvement of the M2 mAChR [30].
• The muscarine-induced increase of ACh release in AChE-deficient junctions was not affected by pertussis toxin, but was completely blocked by MT-7, a specific M1 mAChR antagonist [30].
• In addition muscarine-enhanced sAPPalpha secretion and ERK1/2 activation were inhibited 60 and 80%, respectively, by micromolar concentrations of the phosphatidylinositol 3 kinase (PI-3K) inhibitor wortmannin [31].
• 3. 10 muscarine receptor antagonists with differing relative affinities for M1, M2 and M3 receptors were introduced at 1 mumol/l to inhibit electrically-stimulated acid secretion [32].
• The signalling pathways by which muscarine and epidermal growth factor (EGF) regulate the secretion of the alpha-secretase cleavage product (sAPPalpha) of the amyloid precursor protein (APP) were examined in the human neuroblastoma SH-SY5Y [31].

Analytical, diagnostic and therapeutic context of MUSCARINE

• If muscarinic receptors of chromaffin cells were selectively activated by perfusion with muscarine, 3H-IP3 content and PKC activity were enhanced [33].
• In peripheral airways from wild-type mice (mAChR+/+ mice), muscarine induced a triphasic concentration-dependent response, characterized by an initial constriction, a transient relaxation, and a sustained constriction [19].
• 1. Ca2+ channel modulation by muscarine was investigated in primary cultured embryonic rat hippocampal neurons using the whole-cell variant of the patch-clamp technique [34].
• 1. The role of the endothelium as an effector of the neurogenic cholinergic vasodilatation in submucosal arterioles of the guinea-pig ileum was investigated by measuring changes in arteriolar diameter in response to exogenous application of muscarine or electrical stimulation of the submucosal ganglia [35].
• 2. Axotomy increased M-conductance (gM; muscarine-sensitive, voltage- and time-dependent K+ conductance) by 35% at -30 mV and slowed its deactivation kinetics [36].

References