Human α6β4 nicotinic acetylcholine receptor: heterologous expression and agonist behavior provide insights into the immediate binding site.

Maldifassi, Maria Constanza; Campello, Hugo Rego; Gallagher, Timothy; Lester, Henry A; Dougherty, Dennis A (2023). Human α6β4 nicotinic acetylcholine receptor: heterologous expression and agonist behavior provide insights into the immediate binding site. Molecular pharmacology, 103(6), pp. 339-347. American Society for Pharmacology and Experimental Therapeutics 10.1124/molpharm.123.000672

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Study of α6β4 nicotinic acetylcholine receptors (nAChRs) as a pharmacological target has recently gained interest because of their involvement in analgesia, control of catecholamine secretion, dopaminergic pathways, and aversive pathways. However, an extensive characterization of the human α6β4 nAChRs has been vitiated by technical difficulties resulting in poor receptor expression. In 2020, Knowland and collaborators identified BARP (β-anchoring and regulatory protein), a previously known voltage-gated calcium channel suppressor, as a novel human α6β4 chaperone. Here we establish that co-expression of human BARP with human α6β4 in Xenopus oocytes, resulted in the functional expression of human α6β4 receptors with ACh-elicited currents that allow an in-depth characterization of the receptor using two electrode voltage-clamp electrophysiology together with diverse agonists and receptor mutations. We report: (1) an extended pharmacological characterization of the receptor, and (2) key residues for agonist-activity located in or near the first shell of the binding pocket. Significance Statement The human α6β4 nAChR has attained increased interest because of its involvement in diverse physiological processes and diseases. Although recognized as a pharmacological target, development of specific agonists has been hampered by limited knowledge of its structural characteristics and by challenges in expressing the receptor. By including the chaperone BARP for enhanced expression and employing different ligands, we have studied the pharmacology of α6β4, providing insight into receptor residues and structural requirements for ligands important to consider for agonist-induced activation.

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