Deficiency of nicotinic acetylcholine receptor beta 4 subunit causes autonomic cardiac and intestinal dysfunction.
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.
Wang
Ningshan
N
Department of Physiology and Pharmacology, Sackler Medical School, Genetic Institute, Tel Aviv University, Ramat Aviv, Israel.
Orr-Urtreger
Avi
A
Chapman
Joab
J
Rabinowitz
Ruth
R
Korczyn
Amos D
AD
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001016:Aortic Bodies / Q000378:metabolism; D004195:Disease Models, Animal; D005725:Ganglia, Autonomic / Q000378:metabolism; D005730:Ganglionic Blockers / Q000494:pharmacology; D006331:Heart Diseases / Q000378:metabolism*; D006334:Heart Function Tests; D018738:Hexamethonium / Q000494:pharmacology; D007077:Ileal Diseases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000378:metabolism*
D005730:Ganglionic Blockers; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D018738:Hexamethonium; D000109:Acetylcholine