Muscarinic M3 receptors are coupled to two signal transduction pathways in rat submandibular cells

Laniyonu, Adebayo; Sliwinski-Lis, Eva; Fleming, Norman

doi:10.1016/0922-4106(90)90052-y

Cited by 29 publications

(14 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The striking absence of any significant displacement of [ 3 H]NMS binding by the highly M 1 -selective toxin MT-7 indicates that the guinea pig submandibular gland does not express a significant population of M 1 receptor. This was confirmed by the lack of effect of MT-7 (at 100 nM) on carbachol-stimulated phospho- Although our findings are in agreement with some other studies (Laniyonu et al, 1990;Moriya et al, 1999) it is likely that the makeup of the mACh receptor population in submandibular gland varies from species to species. Thus, a recent study, using methods and range of muscarinic antagonists similar to those used here, reported a significant M 1 mACh receptor subpopulation in canine submandibular gland (Clarke et al, 2003).…”

Section: Tissue-selective Effects Of Muscarinic Antagonists 1261supporting

confidence: 82%

“…Although it is generally accepted that acetylcholine-in- duced phosphoinositide hydrolysis and contraction are mediated almost exclusively by the M 3 receptor in bladder (Harriss et al, 1995;Chess-Williams et al, 2001), some controversy remains over the potential involvement of "non-M 3 " mACh receptors in cholinergic responses of salivary glands (Laniyonu et al, 1990;Watson et al, 1996). We therefore sought clarification of whether the presence of non-M 3 (in particular, M 1 ) muscarinic receptors could be involved in the phosphoinositide response in submandibular gland, using competition radioligand binding assays with a range of the most selective muscarinic ligands available.…”

Section: Tissue-selective Effects Of Muscarinic Antagonists 1261mentioning

confidence: 99%

See 1 more Smart Citation

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Nelson¹,

Gupta²,

Napier³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Binding and functional affinities of the muscarinic acetylcholine (mACh) receptor antagonists darifenacin, tolterodine, oxybutynin, and atropine were assessed in Chinese hamster ovary (CHO) cells expressing the human recombinant M 2 (CHO-m2) or M 3 (CHO-m3) receptors, and in guinea pig bladder and submandibular gland. In [N-methyl-3 H]scopolamine methyl chloride binding studies in CHO cells, darifenacin displayed selectivity (14.8-fold) for the M 3 versus M 2 mACh receptor subtype. Oxybutynin was nonselective, whereas atropine and tolterodine were weakly M 2 -selective (5.1-and 6.6-fold, respectively). Antagonist functional affinity estimates were determined by the inhibition of agonist-induced [ 3 H]inositol phosphate accumulation in CHO-m3 cells and antagonism of the agonist-induced inhibition of forskolin-stimulated cyclic AMP accumulation in CHO-m2 cells. Darifenacin was the most M 3 -selective antagonist (32.4-fold), whereas oxybutynin, atropine, and tolterodine exhibited lesser selectivity. Functional affinity estimates in guinea pig urinary bladder and submandibular salivary gland using indices of phosphoinositide turnover revealed that oxybutynin, darifenacin, and tolterodine each displayed selectivity for the response in the bladder, relative to that seen in the submandibular gland (9.3-, 7.9-, and 7.4-fold, respectively). In contrast, atropine displayed a similar affinity in both tissues. These data demonstrate that in bladder, compared with submandibular gland from a single species, the mACh receptor antagonists darifenacin, tolterodine, and oxybutynin display selectivity to inhibit agonist-mediated phosphoinositide responses. It is proposed that both responses are mediated via M 3 mACh receptor activation and that differential functional affinities displayed by some, but not all, antagonists are indicative of the influence of cell background upon the pharmacology of the M 3 mACh receptor.The cholinergic nervous system is the major pathway by which bladder contraction is initiated in humans (Andersson, 1993). Molecular techniques have identified five muscarinic acetylcholine (mACh) receptor subtypes (m1-m5), whereas pharmacological data can distinguish only four subtypes, denoted as M 1 to M 4 (Caulfield and Birdsall, 1998). Both M 2 and M 3 mACh receptors have been identified in bladder (detrusor) smooth muscle at the level of mRNA (Yamaguchi et al., 1996) and protein, with quantitative immunoprecipitation demonstrating a 75 to 90% predominance of the M 2 subtype in all species studied (Wang et al., 1995). Roles for the majority M 2 receptor population in the contraction of various smooth muscle types (including bladder detrusor) have been proposed, based upon observations in tissues treated with N-2-chloroethyl-4-piperidinyl diphenylacetate selectively to inactivate the M 3 receptor population. Under these conditions M 2 receptor activation may potentiate M 3 -stimulated contraction (via activation of nonselective cation currents or inhibition of Ca 2ϩ -dependent K ϩ efflux), in addition to ...

show abstract

Section: Tissue-selective Effects Of Muscarinic Antagonists 1261supporting

confidence: 82%

Section: Tissue-selective Effects Of Muscarinic Antagonists 1261mentioning

confidence: 99%

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Nelson¹,

Gupta²,

Napier³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Pharmacological, biochemical, and molecular genetic studies indicate that the M 3 receptor subtype plays a key role in mediating increased salivary flow (Laniyonu et al, 1990;Dai et al, 1991;Caulfield, 1993;Watson et al, 1996;Moriya et al, 1999;Matsui et al, 2000;Bockman et al, 2001;Bymaster et al, 2003). However, pharmacological and biochemical studies suggest that M 1 (Watson and Culp, 1994;Culp et al, 1996;Luo et al, 2001;Tobin et al, 2002) and M 5 mAChRs (Flynn et al, 1997;Meloy et al, 2001;Tobin et al, 2002) may also play a role in muscarinic agonist-mediated salivary secretion.…”

mentioning

confidence: 99%

Cholinergic Stimulation of Salivary Secretion Studied with M1 and M3 Muscarinic Receptor Single- and Double-Knockout Mice

Gautam

Heard²,

Cui³

et al. 2004

Molecular Pharmacology

134

View full text Add to dashboard Cite

Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M 1 and M 3 mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M 1 and M 3 receptor single-knockout (KO) mice and newly generated M 1 /M 3 receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M 1 and M 3 receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M 1 and M 3 receptor single-KO mice, indicating that the presence of either M 1 or M 3 receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M 1 or M 3 mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Strikingly, the sialagogue activity of pilocarpine was abolished in M 1 /M 3 receptor double-KO mice. However, salivary glands from M 1 /M 3 receptor double-KO mice remained responsive to stimulation by the ␤-adrenergic receptor agonist, (S)-isoproterenol. Taken together these studies support the concept that a mixture of M 1 and M 3 receptors mediates cholinergic stimulation of salivary flow.

show abstract

“…Notably, cross-talk between these receptors can go in both directions, as M3 muscarinic receptor stimulation can desensitize ␤2-adrenergic receptors via a PKC-dependent phosphorylation of the receptor (20). In addition, M3 receptor stimulation by carbachol promotes a reduction in the isoproterenol-promoted production of cAMP in rodent parotid and submandibular cells (2,21,22).…”

mentioning

confidence: 99%

Isoproterenol and cAMP Block ERK Phosphorylation and Enhance [Ca2+] Increases and Oxygen Consumption by Muscarinic Receptor Stimulation in Rat Parotid and Submandibular Acinar Cells

Soltoff

Hedden

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Salivary glands are innervated by sympathetic and parasympathetic neurons, which release neurotransmitters that promote fluid secretion and exocytosis when they bind to muscarinic and ␤-adrenergic receptors, respectively. Signaling pathways downstream of these receptors are mainly distinct, but there is cross-talk that affects receptor-dependent events. Here we report that the ␤-adrenergic ligand isoproterenol blocks increases in extracellular signal-related kinase (ERK) phosphorylation, a protein kinase C-dependent event promoted by the muscarinic receptor ligand carbachol in freshly dispersed rat parotid acinar cells. The inhibitory action of isoproterenol was reproduced by cAMP stimuli ( Almost all mammalian cells have multiple types of heptahelical G-protein-coupled receptors. The muscarinic receptor and ␤-adrenergic receptor are G-protein-coupled receptors that affect the physiological activities of many cells, and neurotransmitters binding to these receptors produce well defined and mainly separate functional effects in salivary glands, which are innervated by both sympathetic and parasympathetic neurons (1). Parotid acinar cells express M3 muscarinic receptors (2), which are coupled via G q to phospholipase C, and acetylcholine and M3R 2 ligands binding to this receptor initiate the production of the second messengers inositol trisphosphate (InsP 3 ) and diacylglycerol, which elevate the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and activate PKC. The increase in intracellular Ca 2ϩ initiates the opening of ion channels, electrolyte and fluid secretion, and subsequently, the formation of saliva in the oral cavity (3). In contrast, the activation of parotid ␤-adrenergic receptors promotes exocytosis and the release of amylase protein into the oral cavity. ␤-Adrenergic receptors are coupled via G s to adenylyl cyclase, and receptor stimulation generates the production of cAMP (cyclic adenosine monophosphate) and the activation of cAMP-dependent protein kinase (protein kinase A (PKA)) and a signaling cascade downstream of PKA. Muscarinic receptors also can promote exocytosis, but this is more limited than that due to ␤-adrenergic signaling (4). In many cells cAMP also can activate exchange proteins directly activated by cAMP (Epac), which are guanine nucleotide exchange factors for the GTPase Rap. Epac is a cAMP-dependent PKA-independent protein that can mediate various signaling and functional events in salivary glands and other cells (5-7). This can produce complications in evaluating the mechanisms of cross-talk that exist when there is combined muscarinic and ␤-adrenergic signaling, which is a focus of the present study.Isoproterenol has other effects on parotid acinar cells in addition to promoting exocytosis of secretory granules. It

show abstract

Muscarinic M3 receptors are coupled to two signal transduction pathways in rat submandibular cells

Cited by 29 publications

References 9 publications

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Cholinergic Stimulation of Salivary Secretion Studied with M1 and M3 Muscarinic Receptor Single- and Double-Knockout Mice

Isoproterenol and cAMP Block ERK Phosphorylation and Enhance [Ca2+] Increases and Oxygen Consumption by Muscarinic Receptor Stimulation in Rat Parotid and Submandibular Acinar Cells

Contact Info

Product

Resources

About

Muscarinic M3 receptors are coupled to two signal transduction pathways in rat submandibular cells

Cited by 29 publications

References 9 publications

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M3-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M3-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Cholinergic Stimulation of Salivary Secretion Studied with M1 and M3 Muscarinic Receptor Single- and Double-Knockout Mice

Isoproterenol and cAMP Block ERK Phosphorylation and Enhance [Ca2+] Increases and Oxygen Consumption by Muscarinic Receptor Stimulation in Rat Parotid and Submandibular Acinar Cells

Contact Info

Product

Resources

About

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland