The role of loops C and F in interspecies differential pharmacology of the 5‐HT3A receptor

The 5‐Hydroxytryptamine3A (5‐HT3A) receptor is a member of the cys‐loop family of ligand‐gated ion channels. Other members of this family include γ‐aminobutyric acid A (GABAA), γ‐aminobutyric acid C (GABAC), Glycine and nicotinic acetylcholine (nAch) receptors. The 5‐HT3A receptor has been implicated in chemotherapy induced nausea (Leibundgut et al., 1987; Forni et al., 2003), postoperative nausea and vomiting (PONV) (Ang et al., 1998; White et al., 2006), pain syndromes (Dahlof et al., 1998; Faerber et al., 2007), and irritable bowel syndrome (Hammer et al., 1993, Cremonini et al., 2003; Spiller 2006). Despite sharing 84% amino acid identity, mouse and human 5‐HT3A receptors have differential drug sensitivities to 3‐(2‐hydroxy, 4‐methoxybenzylidene)‐anabaseine (2‐OHMBA) and curare. Previously, our laboratory has shown that 2‐OHMBA is a partial agonist at the mouse 5‐HT3A receptor and an antagonist at the human 5‐HT3A receptor (Machu et al., 2001), and that while curare is an antagonist at both mouse and human receptors, there is a 140 fold increase in curare potency at the mouse wild type receptor when compared to the human wild type (Zhang et al., 2007). Using the Xenopus laevis oocyte expression system in the two‐electrode voltage clamp configuration, we have identified a number of individual amino acids within loops C and F that account for interspecies differences in potency and drug response. Presently we are using point‐mutations to probe the role of these critical residues in binding and gating of this ligand‐gated ion channel. Results of this study will enhance our understanding of the structure and function of this receptor and potentially contribute to the development of pharmaceuticals targeting conditions such as PONV, pain syndromes, and chronic diarrhea. Supported by NS 43438