Cross-talk between nicotinic acetylcholine (nAChR) and serotonin (5HT3R) receptors in sympathetic neurons

Abstract

Serotoninergic type 3 receptors (5HT3Rs) are members of the Cys-loop family of ligand-gated ion channels (LGIC), which includes nicotinic ACh, glycine, GABA-A and GABA-C receptors. All members of this family are widely expressed in the central and peripheral nervous systems, where they mostly participate in fast synaptic transmission. Activation of 5HT3Rs on vagal sensory nerve endings affect respiration, circulation, emesis and nociception; and in the central nervous system they are implicated in anxiety, depression, and drug dependence. In contrast, the function of 5HT3Rs in sympathetic neurons has not been fully determined. We discovered that 5HT3Rs interact with nicotinic acetylcholine receptors (nAChRs), the main drivers of the fast cholinergic autonomic synapse, through cross-talk mechanisms. We examined cross-talk by the patch-clamp technique on cultured mouse superior cervical ganglia (SCG) neurons. Co-stimulation of 5HT3Rs and nAChRs resulted in the generation of a combined current that was smaller than arithmetically predicted if the receptors did not interact with one another. This interaction, which we quantified as mean peak amplitude and mean ionic charge, was dependent on activation of 5HT3Rs and nAChRs, and independent of metabotropic receptors, Ca2+ entry and Ca2+ second messenger pathways, and of the direct action of 5HT on nAChRs. Preliminary data using an antibody targeted to the M3-M4 linker region of the 5HT3A subunit revealed that 5HT3Rs and nAChRs possibly cross-talk through physical interactions. These results revealed a potential role of the 5HT3R in the regulation of sympathetic synaptic transmission through cross-talk inhibition of nAChRs.