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Functional activity of the M2 and M4 receptor subtypes in the spinal cord studied with muscarinic acetylcholine receptor knockout mice.
J Pharmacol Exp Ther. 2005 May; 313(2):765-70.JP

Abstract

Stimulation of spinal muscarinic acetylcholine receptors (mAChRs) produces potent analgesia. Both M(2) and M(4) mAChRs are coupled to similar G proteins (G(i/o) family) and play a critical role in the analgesic action of mAChR agonists. To determine the relative contribution of M(2) and M(4) subtypes to activation of G(i/o) proteins in the spinal cord, we examined the receptor-mediated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in M(2) and M(4) subtype knockout (KO) mice. Basal [(35)S]GTPgammaS binding in the spinal cord was similar in the wild-type controls, M(2) and M(4) single-KO, and M(2)/M(4) double-KO mice. The spinal [(35)S]GTPgammaS binding stimulated by either muscarine or oxotremorine-M was not significantly different among three groups of wild-type mouse strains. In M(2) single-KO and M(2)/M(4) double-KO mice, the agonist-stimulated [(35)S]GTPgammaS binding was completely abolished in the spinal cord. Furthermore, the agonist-stimulated [(35)S]GTPgammaS binding in the spinal cord of M(4) single-KO mice was significantly reduced (approximately 15%), compared with that in wild-type controls. On the other hand, the spinal [(35)S]GTPgammaS binding stimulated by a mu-opioid agonist was not significantly different between wild-type and M(2) and M(4) KO mice. This study provides complementary new evidence that M(2) is the most predominant mAChR subtype coupled to the G(i/o) proteins in the spinal cord. Furthermore, these data suggest that a small but functionally significant population of M(4) receptors exists in the mouse spinal cord. The functional activity of these M(4) receptors seems to require the presence of M(2) receptors.

Authors+Show Affiliations

Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15665136

Citation

Chen, Shao-Rui, et al. "Functional Activity of the M2 and M4 Receptor Subtypes in the Spinal Cord Studied With Muscarinic Acetylcholine Receptor Knockout Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 313, no. 2, 2005, pp. 765-70.
Chen SR, Wess J, Pan HL. Functional activity of the M2 and M4 receptor subtypes in the spinal cord studied with muscarinic acetylcholine receptor knockout mice. J Pharmacol Exp Ther. 2005;313(2):765-70.
Chen, S. R., Wess, J., & Pan, H. L. (2005). Functional activity of the M2 and M4 receptor subtypes in the spinal cord studied with muscarinic acetylcholine receptor knockout mice. The Journal of Pharmacology and Experimental Therapeutics, 313(2), 765-70.
Chen SR, Wess J, Pan HL. Functional Activity of the M2 and M4 Receptor Subtypes in the Spinal Cord Studied With Muscarinic Acetylcholine Receptor Knockout Mice. J Pharmacol Exp Ther. 2005;313(2):765-70. PubMed PMID: 15665136.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional activity of the M2 and M4 receptor subtypes in the spinal cord studied with muscarinic acetylcholine receptor knockout mice. AU - Chen,Shao-Rui, AU - Wess,Jürgen, AU - Pan,Hui-Lin, Y1 - 2005/01/21/ PY - 2005/1/25/pubmed PY - 2005/7/6/medline PY - 2005/1/25/entrez SP - 765 EP - 70 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 313 IS - 2 N2 - Stimulation of spinal muscarinic acetylcholine receptors (mAChRs) produces potent analgesia. Both M(2) and M(4) mAChRs are coupled to similar G proteins (G(i/o) family) and play a critical role in the analgesic action of mAChR agonists. To determine the relative contribution of M(2) and M(4) subtypes to activation of G(i/o) proteins in the spinal cord, we examined the receptor-mediated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in M(2) and M(4) subtype knockout (KO) mice. Basal [(35)S]GTPgammaS binding in the spinal cord was similar in the wild-type controls, M(2) and M(4) single-KO, and M(2)/M(4) double-KO mice. The spinal [(35)S]GTPgammaS binding stimulated by either muscarine or oxotremorine-M was not significantly different among three groups of wild-type mouse strains. In M(2) single-KO and M(2)/M(4) double-KO mice, the agonist-stimulated [(35)S]GTPgammaS binding was completely abolished in the spinal cord. Furthermore, the agonist-stimulated [(35)S]GTPgammaS binding in the spinal cord of M(4) single-KO mice was significantly reduced (approximately 15%), compared with that in wild-type controls. On the other hand, the spinal [(35)S]GTPgammaS binding stimulated by a mu-opioid agonist was not significantly different between wild-type and M(2) and M(4) KO mice. This study provides complementary new evidence that M(2) is the most predominant mAChR subtype coupled to the G(i/o) proteins in the spinal cord. Furthermore, these data suggest that a small but functionally significant population of M(4) receptors exists in the mouse spinal cord. The functional activity of these M(4) receptors seems to require the presence of M(2) receptors. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15665136/Functional_activity_of_the_M2_and_M4_receptor_subtypes_in_the_spinal_cord_studied_with_muscarinic_acetylcholine_receptor_knockout_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15665136 DB - PRIME DP - Unbound Medicine ER -