A first step towards the understanding of the 5-HT3 receptor subunitheterogeneity from a computational point of view

The functional serotonin type-3 receptor (5-HT3-R), which is the target of many neuroactive drugs, isknown to be a homopentamer made of five identical subunits A (5-HT3A-R) or a binary heteropentamermade of subunits A and B (5-HT3A/B-R) with a still debated arrangement and stoichiometry. Thiscomplex picture has been recently further complicated by the discovery of additional 5-HT3-R subunits,C, D, and E, which, similarly to the B subunit, are apparently able to form functional receptors only ifco-expressed with subunit A. Being the binding site for both serotonin and antagonists (i.e. drugs)located at the extracellular interface between two adjacent subunits, the large variability of the 5-HT3-Rcomposition becomes a crucial issue, since it can originate many different interfaces providing nonequivalentligand binding sites and complicating the pharmacological modulation. Here, the different5-HT3-R interfaces are analysed, on the bases of the structural conformations of previously built 3Dhomology models and of the known subunit sequences, by addressing their physicochemicalcharacterization. The results confirm the presence of an aromatic cluster located in the core of the A–Ainterface as a key determinant for having an interface both stable and functional. This is used as adiscriminant to make hypotheses about the capability of all the other possible interfaces constituted bythe known 5-HT3-R sequences A, B, C, D, and E to build active receptors.