The fifth subunit of the (α4β2) β2 nicotinic ACh receptor modulates maximal ACh responses.

Background And Purpose: The fifth subunit in the (α4β2) α4 nicotinic ACh receptor (nAChR) plays a determining role in the pharmacology of this nAChR type. Here, we have examined the role of the fifth subunit in the ACh responses of the (α4β2) β2 nAChR type.

Experimental Approach: The role of the fifth subunit in receptor function was explored using two-electrode voltage clamp electrophysiology, along with subunit-targeted mutagenesis and the substituted cysteine scanning method applied to fully linked (α4β2) β2 receptors.

Non-equivalent ligand selectivity of agonist sites in (α4β2)2α4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.

The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR type in the brain, and this receptor type exists in alternate (α4β2)2α4 and (α4β2)2β2 forms, which are activated by agonists with strikingly differing efficacies. Recent breakthroughs have identified an additional operational agonist binding site in the (α4β2)2α4 nAChR that is responsible for the signature sensitivity of this receptor to activation by agonists, yet the structural mechanisms determining agonist efficacy at this receptor type are not yet fully understood. In this study, we characterized the ligand selectivity of the individual agonist sites of the (α4β2)2α4 nAChR to determine whether differences in agonist selectivity influence agonist efficacy.

Allosteric modulators of α4β2 nicotinic acetylcholine receptors: a new direction for antidepressant drug discovery.

Allosteric modulation of ligand-gated ion channels has been intensively studied in the past three decades and is now an established strategy to control receptor function in numerous disease states. Allosteric sites on the GABA(A) receptor are targets for widely prescribed drugs that are used for a variety of pathophysiological states including insomnia and epilepsy. Modulators might be especially valuable to control receptors for which the design of selective orthosteric drugs has proven difficult due to safety issues (e.