Muscarinic Receptors—Characterization, coupling and function

Caulfield, Malcolm P.

doi:10.1016/0163-7258(93)90027-b

Cited by 1,163 publications

(955 citation statements)

References 358 publications

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“…16,17 Notably, the outcome of nicotinic or muscarinic receptor activation can be contradictory, because individual members of each class of ACh receptors differ in their ligand-binding affinities and downstream effectors (reviewed in ref. [18][19][20]. Furthermore, the repertoire of ACh receptors expressed in non-neuronal cells changes during cell development, leading to reciprocal changes in the cellular functions controlled by autocrine/paracrine ACh (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

et al. 2011

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Acetylcholine (ACh) regulates vital functions of T cells by acting on the nicotinic and muscarinic classes of cholinergic receptors, nAChR and mAChRs, respectively. This study was performed in murine splenic T cells. In freshly isolated CD4 and CD8 T cells, we detected mRNAs encoding a5, a9, a10, b1, b2, b4 nAChR subunits and M 1 , M 3 , M 4 and M 5 mAChR subtypes, whereas a2 was detected only in CD8 T cells. In vitro activation of CD4 T cells through T-cell receptor (TCR)/CD3 cross-linking was associated with the appearance of a4 and a7, upregulation of a5, a10, b4, M 1 and M 5 and downregulation of a9 and b2, whereas in vitro activation of CD8 T cells also featured the appearance of a4 and a7, as well as upregulation of a2, a5, b4, M 1 and M 4 , and downregulation of a10, b1, b2 and M 3 . In vitro polarization toward T helper (Th) 1 lineage was associated with a decrease of b2, b4 and M 3 expression; that toward Th2 cells with downregulation of a9 and M 3 , and upregulation of M 1 and M 5 ; and that toward Th17 phenotype with downregulation of a9, a10, b2 and M 3 mAChR. Polarized T cells also expressed a4, but not a1, a2, a3, a6, b3 or M 2 . To determine the role of cholinergic receptors in mediating the immunoregulatory action of autocrine/paracrine ACh, we analyzed the effects of nicotinic and muscarinic agonists ± antagonists on cytokine production in the CD4 þ CD62L þ T cells co-stimulated via TCR/CD3 cross-linking. The nicotinergic stimulation upregulated interferon-g (IFN-g) and downregulated interleukin (IL)-17 secretion, whereas the muscarinic stimulation enhanced IL-10 and IL-17 and inhibited INF-g secretion. These results demonstrated plasticity of the T-cell cholinergic system.

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Section: Introductionmentioning

confidence: 99%

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

et al. 2011

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“…Five subtypes of muscarinic receptor have been identi¢ed by molecular techniques [Caul¢eld, 1993]. M 2 and M 3 receptor subtypes predominate in the detrusor muscle, with the population of the M 2 subtype receptor in detrusor muscle greater than the M 3 subtype.…”

Section: Introductionmentioning

confidence: 99%

M₂ mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

Braverman¹,

Лебед²,

Linder³

et al. 2006

Neurourology and Urodynamics

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Aims: Previous studies have shown increased density of M 2 receptors in hypertrophied rat bladders that possess an M 2 contractile phenotype. The aim of the current study is to determine whether human bladders with an M 2 contractile phenotype also have a greater density of bladder M 2 receptors. Materials and Methods: Human bladders were obtained from 24 di¡erent organ transplant donors. Darifenacin and methoctramine a⁄nity was determined by the rightward shift of cumulative carbachol concentration contractile response curves for each bladder. Radioligand binding and immunoprecipitation was used to quantify M 2 and M 3 subtypes in isolated detrusor muscle and urothelium. In addition, pig bladder muscle and urothelial receptors were quanti¢ed for comparison. Results: In the human urothelium total, M 2 and M 3 muscarinic receptor density is signi¢cantly negatively correlated with the a⁄nity of darifenacin for inhibition of contraction of the detrusor muscle. In the detrusor muscle there is no correlation between receptor density and darifenacin a⁄nity for inhibition of contraction. Muscarinic receptor density is greater in the muscle than in the urothelium in human bladders whereas in the pig bladder the density is greater in the urothelium than in the muscle. Conclusions: The greater density of urothelial muscarinic receptors in human bladders with lower darifenacin a⁄nity, indicative of a greater contribution of M 2 receptors to the contractile response, points towards a possible role of the urothelium in controlling M 2 mediated contractile phenotype. In comparison between human and pig bladders, the distribution of muscarinic receptor subtypes in the muscle and urothelium are quite di¡erent.

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“…The five types of mammalian muscarinic receptors, m1-m5, differ in primary structure as determined by molecular cloning (Caulfield, 1993). The molecularly defined m1, m2, and m3 receptors correlate with the pharmacologically defined binding M 1 , M 2 , and M 3 sites in mammalian tissues (Caulfield, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…The molecularly defined m1, m2, and m3 receptors correlate with the pharmacologically defined binding M 1 , M 2 , and M 3 sites in mammalian tissues (Caulfield, 1993). It is well established that 'odd-numbered' muscarinic receptors (M 1 -M 3 -M 5 ) typically couple via the a subunits of the G q/11 family to activate phospholipase C (PLC), stimulating phosphoinositide (PI) hydrolysis (Caulfield and Birdsall, 1998).…”

Section: Introductionmentioning

confidence: 99%

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

Galeotti¹,

Bartolini²,

Ghelardini³

2002

Neuropsychopharmacol

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The cellular events involved in muscarinic analgesia were investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) pretreatment with antisense oligonucleotides (aODNs) against the a subunit of G q and G 11 proteins prevented the analgesia induced by physostigmine and oxotremorine. Furthermore, administration of the phospholipase C (PLC) inhibitor U-73122, as well as the injection of an aODN complementary to the sequence of PLCb 1 , antagonized the increase of the pain threshold induced by both cholinomimetic drugs. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or treatment with heparin, an IP 3 receptor antagonist, the antinociception induced by physostigmine and oxotremorine was dose-dependently antagonized. I.c.v. pretreatment with TMB-8, a blocker of Ca 2+ release from intracellular stores, prevented the increase of pain threshold induced by the investigated cholinomimetic drugs. Coadministration of Ca 2+ restored the muscarinic analgesia in LiCl, heparin, and TMB-8-preatreated mice. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitor calphostin C, resulted in a dose-dependent enhancement of physostigmine-and oxotremorine-induced antinociception. The administration of PKC activators, such as PMA and PDBu, dose dependently prevented the cholinomimetic drug-induced increase of pain threshold. Neither aODNs nor pharmacological treatments employed produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate a role for the PLC-IP 3 pathway in central muscarinic analgesia in mice. Furthermore, activation of PKC by cholinomimetic drugs may represent a pathway of negative modulation of muscarinic antinociception.

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Muscarinic Receptors—Characterization, coupling and function

Cited by 1,163 publications

References 358 publications

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

M₂ mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

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Muscarinic Receptors—Characterization, coupling and function

Cited by 1,163 publications

References 358 publications

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

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M₂ mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors