Hallucinogen actions on 5-HT receptors reveal distinct mechanisms of activation and signaling by G protein-coupled receptors

We review the effect of some key advances in the characterization of molecular mechanisms of signaling by G protein-coupled receptors (GPCRs) on our current understanding of mechanisms of drugs of abuse. These advances are illustrated by results from our ongoing work on the actions of hallucinogens on serotonin (5-HT) receptors. We show how a combined computational and experimental approach can reveal specific modes of receptor activation underlying the difference in properties of hallucinogens compared with nonhallucinogenic congeners. These modes of activation-that can produce distinct ligand-dependent receptor states-are identified in terms of structural motifs (SM) in molecular models of the receptors, which were shown to constitute conserved functional microdomains (FM). The role of several SM/FMs in the activation mechanism of the GPCRs is presented in detail to illustrate how this mechanism can lead to ligand-dependent modes of signaling by the receptors. Novel bioinformatics tools are described that were designed to support the quantitative mathematical modeling of ligand-specific signaling pathways activated by the 5-HT receptors targeted by hallucinogens. The approaches for mathematical modeling of signaling pathways activated by 5-HT receptors are described briefly in the context of ongoing work on detailed biochemical models of 5-HT2A, and combined 5-HT2A/5-HT1A, receptor-mediated activation of the MAPK 1,2 pathway. The continuing need for increasingly more realistic representation of signaling in dynamic compartments within the cell, endowed with spatio-temporal characteristics obtained from experiment, is emphasized. Such developments are essential for attaining a quantitative understanding of how the multiple functions of a cell are coordinated and regulated, and to evaluate the specifics of the perturbations caused by the drugs of abuse that target GPCRs.