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Vol. 63, Issue 3, 574-580, March 2003

Deficiency of Nicotinic Acetylcholine Receptor beta 4 Subunit Causes Autonomic Cardiac and Intestinal Dysfunction

Ningshan Wang, Avi Orr-Urtreger, Joab Chapman, Ruth Rabinowitz, and Amos D. Korczyn

Department of Physiology and Pharmacology (N.W., J.C., R.R., A.D.K.), Sackler Medical School, Genetic Institute and Departments of Pediatrics (A.O.-U.) and Neurology (J.C., A.D.K.), Tel Aviv Sourasky Medical Center, and the Sieratzki Chair of Neurology (A.D.K.), Tel Aviv University, Ramat Aviv, Israel

Neuronal nicotinic acetylcholine receptors (nAChR) are composed of 12 subunits (alpha 2-alpha 10 and beta 2-beta 4), which play the central role in autonomic transmission. beta 4 subunits are abundantly expressed in autonomic ganglia, forming acetylcholine binding sites and ion channels with alpha 3 or alpha 3 and alpha 5 subunits as pentameric receptors. To investigate the physiological and pharmacological properties of beta 4 subunits in autonomic ganglia, we measured autonomic functions in knockout mice lacking nAChR subunit beta 4 (beta 4-/-) and wild-type mice. beta 4-/- mice had an attenuated bradycardiac response to high frequency (60 pulse/s) vagal stimulation, as well as an increased sensitivity to hexamethonium blockade at low dose (3 mg/kg) and a reduced ileal contractile response to the nicotinic agonists cytisine, dimethylphenylpiperazinium iodide, nicotine (10 mg/kg each), and epibatidine (0.1 mg/kg). The results suggest that beta 4 subunits are important components of nAChRs in autonomic ganglia. Deficiency of beta 4 subunits altered ion channel properties, conductance, and sensitivity and affinity of receptors to agonists and antagonists, affecting ganglionic transmission.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics