title: M2 muscarinic ACh receptors sensitive BK channels mediate cholinergic inhibition of type II vestibular hair cells.
abstract: There are two types of hair cells in the sensory epithelium of vestibular end organ. Type II vestibular hair cell (VHC II) is innervated by the efferent nerve endings, which employ a cholinergic inhibition mediated by SK channels through the activation of α9-containing nAChR. Our previous studies demonstrated that a BK-type cholinergic inhibition was present in guinea pig VHCs II, which may be mediated by an unknown mAChR. In this study, BK channel activities triggered by ACh were studied to determine the mAChR subtype and function. We found the BK channel was insensitive to α9-containing nAChR antagonists and m1, m3, m4 muscarinic antagonists, but potently inhibited by the m2 muscarinic antagonist. Muscarinic agonists could mimic the effect of ACh and be blocked by m2 antagonist. cAMP analog activated the BK current and adenyl cyclase (AC) inhibitor inhibited the ACh response. Inhibitor of Giα subunit failed to affect the BK current, but inhibitor of Giα and Giβγ subunits showed a potent inhibition to these currents. Our findings provide the physiological evidence that mAChRs may locate in guinea pig VHCs II, and m2 mAChRs may play a dominant role in BK-type cholinergic inhibition. The activation of m2 mAChRs may stimulate Giβγ-mediated excitation of AC/cAMP activities and lead to the phosphorylation of Ca(2+) channels, resulting in the influx of Ca(2+) and opening of the BK channel.
authors.affiliation: Department of Otolaryngology, Union Hospital of Tongji Medical College, Hua-Zhong University of Science and Technology, Wuhan 430022, People's Republic of China.
authors.forename: Chang-Kai
authors.initials: CK
authors.lastname: Guo
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D055724:Electrophysiological Phenomena; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006168:Guinea Pigs; D018069:Hair Cells, Vestibular / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D000109:Acetylcholine