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CELLULAR AND MOLECULAR

Functional Activity of the M₂ and M₄ Receptor Subtypes in the Spinal Cord Studied with Muscarinic Acetylcholine Receptor Knockout Mice

Departments of Anesthesiology (S.-R.C., H.-L.P.) and Neural and Behavioral Sciences (H.-L.P.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Molecular Signaling Section (J.W.), Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland

Stimulation of spinal muscarinic acetylcholine receptors (mAChRs) produces potent analgesia. Both M₂ and M₄ 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 M₂ and M₄ subtypes to activation of G_i/o proteins in the spinal cord, we examined the receptor-mediated guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding in M₂ and M₄ subtype knockout (KO) mice. Basal [³⁵S]GTPS binding in the spinal cord was similar in the wild-type controls, M₂ and M₄ single-KO, and M₂/M₄ double-KO mice. The spinal [³⁵S]GTPS binding stimulated by either muscarine or oxotremorine-M was not significantly different among three groups of wild-type mouse strains. In M₂ single-KO and M₂/M₄ double-KO mice, the agonist-stimulated [³⁵S]GTPS binding was completely abolished in the spinal cord. Furthermore, the agonist-stimulated [³⁵S]GTPS binding in the spinal cord of M₄ single-KO mice was significantly reduced (15%), compared with that in wild-type controls. On the other hand, the spinal [³⁵S]GTPS binding stimulated by a µ-opioid agonist was not significantly different between wild-type and M₂ and M₄ KO mice. This study provides complementary new evidence that M₂ 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 M₄ receptors exists in the mouse spinal cord. The functional activity of these M₄ receptors seems to require the presence of M₂ receptors.

Address correspondence to: Dr. Hui-Lin Pan, Department of Anesthesiology, H187, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail: hpan{at}psu.edu

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