Identifying Motifs Essential for Selective Activation of Nicotinic Acetylcholine Receptors

Abstract

Neuronal Nicotinic acetylcholine receptors (nAChRs) are found throughout the brain and have vital roles in memory and learning. In addition, these ligand gated ion channel are major targets of drug research for neurological disorders. Here, the two stoichiometries of α4β2 nAChRs expressed in Xenopus oocytes were probed using two agonists that display stoichiometry selectivity: Sazetidine A and NS9283. The results from these studies led to the following conclusions that may be generalized to the nAChR family: 1) an agonist must be bound to each α subunit in the receptor in order to fully activate the receptor and 2) three key residues located on the complementary side of the subunit dictate agonist selectivity. Through better understanding of agonist binding, more potent and selective responses with minimized off target responses can be obtained.

Additional details