title: Identification of a new amino acid residue capable of modulating agonist efficacy at the homomeric nicotinic acetylcholine receptor, alpha7.
abstract: Neuronal nicotinic receptors (nAChRs) have been implicated in pathology associated with neurological diseases and aberrant cognitive states such as addiction and schizophrenia. The design of subtype-specific cholinergic drugs is dependent on identification of key amino acids that play a significant role in determining subunit-specific agonist efficacy. 1,1-Dimethyl-4-phenylpiperazinium (DMPP) and a series of piperazium (PIP)-derived cholinergic agonists (1,1 dimethyl-4-acetylpiperizinium iodide, EthylPIP, PropylPIP, and ButylPIP) were used to identify a site (position 84) in homomeric neuronal nAChRs, which is a partial determinant of pharmacological specificity. In contrast to absolutely conserved amino acids within the nicotinic superfamily, the amino acid in position 84 can be polar or nonpolar. The addition of one methylene to PropylPIP to form ButylPIP eliminated channel activation of but not binding to the chick alpha7 homomeric nAChR (leucine in position 84). In rat alpha7 (glutamine in position 84), ButylPIP was an agonist. 1, 1-Dimethyl-4-phenylpiperazinium, a structural analog of ButylPIP, activates the rat alpha7 but is a weak partial agonist of the chick alpha7. Mutation of the chick alpha7 (L84Q) restored activation by ButylPIP, and the corresponding mutation in rat alpha7 (Q84L) abolished activation by ButylPIP. These mutations had moderate effects on the apparent affinity for acetylcholine, increasing its affinity for chick alpha7 and decreasing it for rat alpha7. Thus, the amino acid in position 84 (a residue on the periphery of the highly conserved loop A of the cys-loop superfamily of receptors) can potentially be exploited to produce subtype-specific drugs and can provide insights into the structure of the binding domain.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Vazquez
authors.forename: R E
authors.initials: RE
authors.lastname: Oswald
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002645:Chickens; D004246:Dimethylphenylpiperazinium Iodide / Q000378:metabolism; D008969:Molecular Sequence Data; D018722:Nicotinic Agonists / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018722:Nicotinic Agonists; D010879:Piperazines; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide; D000109:Acetylcholine