G proteins as drug targets

The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical receptor by the ap propriate agonists, the cognate G proteins undergo a cycle of activation an d deactivation; the alpha-subunits and the beta gamma-dimers interact seque ntially with several reaction partners (receptor, guanine nucleotides and e ffecters as well as regulatory proteins) by exposing appropriate binding si tes. For most of these domains, low molecular weight ligands have been iden tified that either activate or inhibit signal transduction. These ligands i nclude short peptides derived from receptors, G protein subunits and effect ers, mastoparan and related insect venoms, modified guanine nucleotides, su ramin analogues and amphiphilic cations. Because compounds that act on G pr oteins may be endowed with new forms of selectivity, we propose that G prot ein subunits may therefore be considered as potential drug targets.