Disease relevance of Oxotremorine M

• Muscarinic receptor-mediated NF-kappaB activation was confirmed by observing the translocation of the active subunit (p65) of NF-kappaB to the nucleus by the muscarinic agonist, oxotremorine M (oxoM), in SH-SY5Y neuroblastoma cells expressing muscarinic receptors that are predominantly of the M3 subtype [1].
• Exposure to either pertussis toxin or the anti-Go alpha antiserum 9072 but not to cholera toxin or the anti-Gs alpha antiserum 1191 reduced the high-affinity binding of oxotremorine M to muscarinic receptors [2].
• Exposure of cells permeabilized with digitonin, streptolysin-O, or the alpha-toxin from Staphylococcus aureus to oxotremorine-M (Oxo-M) for 30 min resulted in a 25-30% reduction in the number of cell surface mAChRs, as monitored by the loss of N[3H]methylscopolamine ([3H]NMS) binding sites [3].
• 2. Acetylcholine (ACh) or nicotine, and muscarine or oxotremorine-M (OX-M) induced membrane depolarization with rapid and slow time courses respectively, followed by repetitive generation of action potentials in the ganglion cell [4].
• By comparing the response magnitude and the effectiveness in evoking a response, the rank order for evoking excitation, the primary response, was found to be: OM > CCh > ACh approximately McN, which is consistent with that (OM > CCh > McN) for facilitating lordosis reported by others [5].

Psychiatry related information on Oxotremorine M

• The M2 agonists Oxotremorine-M and Cisdioxolane significantly increased REM sleep percentage [6].
• Locomotor activity was increased by scopolamine and oxotremorine-M administration in all treatments [7].
• The maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was significantly increased in Alzheimer's disease superior temporal cortex, suggesting an enhanced muscarinic M2 receptor-G-protein coupling efficiency in this region [8].

High impact information on Oxotremorine M

• Modulation of N- and L-type Ca2+ channels by oxotremorine-M (oxo-M) acting on muscarinic receptors and norepinephrine (NE) acting on alpha-adrenergic receptors was studied in superior cervical ganglion neurons [9].
• To study the potential role of the M(3) muscarinic receptor subtype in cholinergic stimulation of insulin release, we initially examined the effect of the muscarinic agonist, oxotremorine-M (Oxo-M), on insulin secretion from isolated pancreatic islets prepared from wild-type (WT) and M(3) receptor-deficient mice (M3(+/-) and M3(-/-) mice) [10].
• Pretreatment with oxotremorine-M, a selective agonist of muscarinic receptors that are expressed endogenously in these cells, did not affect the accumulation of p53 but greatly attenuated caspase-3 activation and protected from cell death to nearly the same extent as treatment with a general caspase inhibitor [11].
• Likely the most proximal of these events to muscarinic receptor activation, mitochondrial Bax accumulation, also was attenuated by oxotremorine-M treatment after treatment with H(2)O(2) or rotenone [11].
• In contrast, when oxotremorine-M-stimulated phosphoinositide hydrolysis was inhibited by depletion of extracellular Ca2+, no reduction in the extent of receptor sequestration was observed [12].

Chemical compound and disease context of Oxotremorine M

• Incubation of SH-SY5Y neuroblastoma cells with oxotremorine-M resulted in a time-dependent endocytosis of both muscarinic receptors and alpha subunits of G0 and G11, but not of isoforms of phosphoinositide-specific phospholipase C, into a subfraction of smooth endoplasmic reticulum (V1) [13].
• In control tissues, isoproterenol (1 microM) only slightly inhibited contractions in response to oxotremorine-M; however, in pertussis toxin-treated tissues, isoproterenol exhibited an enhanced inhibition of the concentration-effect curve [14].
• Treatment of the ileum with pertussis toxin caused a small increase in the contractile response to oxotremorine-M when measured without prior exposure to acetylcholine [15].
• Himbacine was a potent blocker of oxotremorine-M-mediated cyclic AMP inhibition in rat striatum (4.4 nM) and in N1E-115 neuroblastoma cells (10.6 nM), responses mediated by M4 receptors [16].
• We also measured the effects of pertussis toxin treatment on the ability of isoproterenol to inhibit the contraction elicited by a single concentration of either histamine (0.3 microM) or oxotremorine-M (40 nM) in both the ileum and trachea [17].

Biological context of Oxotremorine M

• Addition of oxotremorine-M to permeabilized cells resulted in muscarinic receptor sequestration and down-regulation [12].
• Atropine, oxotremorine, and oxotremorine-M antagonized the rate of alkylation of muscarinic receptors in a manner that was consistent with competitive inhibition [18].
• In these latter two subtypes, BM5 inhibited oxotremorine-M-stimulated PI turnover with IC50 values of 10-20 microM [19].
• At low concentrations (e.g. 0.1-1 microM oxotremorine-M), 'burst-mode' activity comprised regular individual AMPA receptor-mediated depolarizing events, each generating several action potentials [20].
• In adult neurones, bath-application of the mAChR agonist oxotremorine-M (OXO-M; 10 microM), or the selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 10 microM) evoked similar membrane depolarization and inhibition of evoked excitatory postsynaptic potentials (EPSPs) [21].

Anatomical context of Oxotremorine M

• The ability of oxotremorine-M to activate phospholipase C, via m1, m3, and m5 receptors was also unchanged more than a year after cholinergic denervation of the hippocampus [22].
• In addition, the full agonists, oxotremorine-M and carbamoylcholine, were more potent stimulators of inositol phosphate release in the neostriatum than in the cerebral cortex [23].
• The incorporation of [3H]serine into lipids, water-soluble metabolites and proteins by the human neuroblastoma cell line LA-N-1 exposed to oxotremorine-M, a muscarinic agonist, was investigated [24].
• By reconstituting M currents in Xenopus oocytes, we observed that stimulation of coexpressed M1 receptors with 10 microm oxotremorine M (oxo-M) induces a positive shift (4-30 mV, depending on which KCNQ channels are expressed) in the conductance-voltage relationship (G-V) of KCNQ channels [25].
• Neither oxotremorine-M nor acetylcholine caused a redistribution of protein kinase C activity between the cytosol and membrane compartments [24].

Associations of Oxotremorine M with other chemical compounds

• Potentiation of oxotremorine-M-stimulated inositol lipid hydrolysis observed in the presence of either norepinephrine or isoproterenol was reduced in the absence of added Ca2+ [26].
• The highest degrees of positive cooperativity were observed between (-)-eburnamonine and pilocarpine and (-)-eburnamonine and oxotremorine-M on the M2 receptors (25- and 7-fold increases in affinity, respectively) and between brucine and pentylthio-TZTP on the M2 and brucine and carbachol on the M1 receptors (8-fold increases in affinity) [27].
• When assayed under conditions similar to those employed for the fluorescence measurements, EGTA also inhibited both the basal and oxotremorine-M-stimulated release of inositol phosphates by 45-61% [28].
• Despite the low affinity of bethanechol for the M2 receptor, it was an efficacious agonist (maximal response equivalent to that of oxotremorine-M; relative efficacy = 0.6) at this subtype, whereas it was a partial agonist (60%) with lesser efficacy in the clonal M4 system [29].
• In the absence of retigabine, oxotremorine M depolarised the neurons and elicited action potential discharges in 8 of 23 neurons; in its presence, oxotremorine M still caused equal depolarisations, but always failed to trigger action potentials [30].

Gene context of Oxotremorine M

• Occupation of just 15% of the M1 receptors in mouse hippocampus was required for maximal efficacy of oxotremorine-M-stimulated GTP-gamma-35S binding indicating a substantial level of spare receptors [31].
• Pretreatment of the cells with muscarinic receptor agonist, oxotremorine M (Oxo-M), enhanced IL-2 production induced by phorbol 12-myristate 13-acetate (PMA)/A23187, while Oxo-M by itself did not affect IL-2 production [32].
• Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons [33].
• However, in the presence of the M2 and M4 subtype-preferring antagonist himbacine, oxotremorine-M caused a large increase in the sIPSC frequency [34].
• In M2 or M4 single-KO mice, oxotremorine-M produced a variable effect on sIPSCs; it increased the frequency of sIPSCs in some cells but decreased the sIPSC frequency in other neurons [34].

Analytical, diagnostic and therapeutic context of Oxotremorine M

• Perfusion of hearts with BM 123A for 30 min caused a lack of sensitivity of the heart to the muscarinic agonist oxotremorine-M and an 80% alkylation of muscarinic receptors as measured by the reduction in the binding capacity of N-[3H]methylscopolamine [35].
• The persistent excitatory effects of the muscarinic agonist oxotremorine-M were investigated in guinea-pig olfactory cortex neurons in vitro (28-30 degrees C) using a single-microelectrode current-clamp/voltage-clamp technique [36].

References