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MOLECULAR AND GENOMIC |
4-containing nicotinic receptors
1 Division of Neurology
2 Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013-4496, USA
3 Division of Science, Chandler-Gilbert Community College, Chandler, AZ 85225, USA
4 Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ 85724-5017, USA
Naturally expressed nicotinic acetylcholine receptors (nAChR) containing 
4 subunits (4*-nAChR) in combination with ß2 subunits (4ß2-nAChR) are among the most abundant, high-affinity nicotine binding sites in the mammalian brain. ß4 subunits are also richly expressed and colocalize with 4 subunits in several brain regions implicated in behavioural responses to nicotine and nicotine dependence. Thus, 4ß4-nAChR also may exist and play important functional roles. In this study, properties were determined of human 4ß2- and 4ß4-nAChR heterologously expressed de novo in human SH-EP1 epithelial cells. Whole-cell currents mediated via human 4ß4-nAChR have 
4-fold higher amplitude than those mediated via human 4ß2-nAChR and exhibit much slower acute desensitization and functional rundown. Nicotinic agonists induce peak whole-cell current responses typically with higher functional potency at 4ß4-nAChR than at 4ß2-nAChR. Cytisine and lobeline serve as full agonists at 4ß4-nAChR but are only partial agonists at 4ß2-nAChR. However, nicotinic antagonists, except hexamethonium, have comparable affinities for functional 4ß2- and 4ß4-nAChR. Whole-cell current responses show stronger inward rectification for 4ß2-nAChR than for 4ß4-nAChR at a positive holding potential. Collectively, these findings demonstrate that human nAChR ß2 or ß4 subunits can combine with 4 subunits to generate two forms of 4*-nAChR with distinctive physiological and pharmacological features. Diversity in 4*-nAChR is of potential relevance to nervous system function, disease, and nicotine dependence.
(Received 2 June 2006;
accepted after revision 5 July 2006;
first published online 6 July 2006)
Corresponding author J. Wu: Neurophysiology Laboratory, Division of Neurology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013-4496, USA. Email: jie.wu{at}chw.edu
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