Allosteric modulation of the 5-HT(3) receptor

Abstract

5-Hydroxytryptamine type 3 (5-HT(3)) receptors are ligand-gated ion channels that play important roles in depression, anxiety, substance abuse, emesis, inflammatory pain, spinal nociception, gastrointestinal function, and cardiovascular reflexes. Probably the most studied modulators of 5-HT(3) receptors are the high affinity competitive 'setron' antagonists typified by ondansetron. However, there exists a broad range of compounds that modulate the 5-HT(3) receptor, not through the orthosteric site but by binding to allosteric sites. Most notable are therapeutic compounds ascribed to certain targets but that allosterically modulate 5-HT(3) receptors at clinically relevant concentrations.

Figure 1. Ethanol increases the number of open single-channel events

Left, Cell-attached recordings of human 5-HT₃A(QDA)-mediated currents evoked by 100 μM 5-HT in the absence (A) or presence (B) of 25 mM ethanol. Twenty second examples of single-channel activity with an expanded view of a burst (left panel). Dotted lines indicating closed and open states. Right, all-points histograms for the 20 s recordings of 5-HT₃A(QDA)-mediated currents evoked by 100 μM 5-HT shown in left panel. Histograms were fitted by two Gaussians, percentages of events in the closed and open states are shown. Figure reproduced, with permission, from Feinberg-Zadek and Davies [13].

Figure 2. Kinetic model of 5-HT₃A receptor function

The major states and transitions required to account for the actions of agonists on 5-HT₃ receptors are shown in black. The minor transitions, which are shown in grey, are assumed to be possible, but negligible Values of rate constants (denoted above and below arrows) determined from macroscopic current experiments with rapid solution exchange are given in Solt et al. [40].