Pharmacological Evaluation of Choline on α4β2 Neuronal Nicotinic Acetylcholine Receptors

Abstract

Choline is the precursor and metabolite of acetylcholine (ACh), the endogenous neurotransmitter responsible for activation of neuronal nicotinic acetylcholine receptors (nAChRs). Choline is known to activate some nAChRs, which suggests that it may play a role in neurotransmission beyond being a precursor/metabolite. Using electrophysiological techniques, this study investigates effects of choline on currently known α4β2 nAChRs stochiometries ― (α4)3(β2)2 and (α4)2(β2)3. The results suggests that choline activates (α4)3(β2)2 nAChRs with EC50 of 0.4mM and a maximal efficacy of 4%. In contrast, it did not produce any response on (α4)2(β2)3. When co-applied with ACh we revealed that low concentrations of choline potentiated currents induced by 1 µM and 10 µM ACh, but inhibited by choline in concentrations of 1mM or higher. Choline was also tested on mutant receptors engineered to only have α4α4 or α4β2-like binding sites in (4)3(23M)2 or (43M)3(2)2 respectively. On these mutant constructs, choline activated the (4)3(23M)2 receptors with EC50 of 0.3mM and a maximum response of 4%. In contrast, choline had no effect on (43M)3(2)2 nAChRs. Overall our results show that at least one α4α4 binding site is required to notice choline activity on α4β2 nAChRs. Choline also modulates ACh-mediated activation of nAChRs.