Cross Talk between a7 and a3b4 Nicotinic Receptors Prevents Their Desensitization in Human Chromaffin Cells

Abstract

The physical interaction and functional cross talk among the different subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) expressed in the various tissues is unknown. Here, we have investigated this issue between the only two nAChRs subtypes expressed, the a7 and a3b4 subtypes, in a human native neuroendocrine cell (the chromaffin cell) using electrophysiological patch-clamp, fluorescence, and Förster resonance energy transfer (FRET) techniques. Our data show that a7 and a3b4 receptor subtypes require their mutual and maximal efficacy of activation to increase their expression, to avoid their desensitization, and therefore, to increase their activity. In this way, after repetitive stimulation with acetylcholine (ACh), a7 and a3b4 receptor subtypes do not desensitize, but they do with choline. The nicotinic current increase associated with the a3b4 subtype is dependent on Ca21. In addition, both receptor subtypes physically interact. Interaction and expression of both subtypes are reversibly reduced by tyrosine and serine/threonine phosphatases inhibition, not by Ca21. In addition, expression is greater in human chromaffin cells from men compared to women, but FRET efficiency is not affected. Together, our findings indicate that human a7 and a3b4 subtypes mutually modulate their expression and activity, providing a promising line of research to pharmacologically regulate their activity.