G protein antagonists

Heterotrimeric G proteins couple membrane-bound heptahelical receptors to t heir cellular effector systems (ion channels or enzymes generating a second messenger). In current pharmacotherapy, the input to G protein-regulated s ignalling is typically manipulated by targeting the receptor with appropria te agonists or antagonists and, to a lesser extent, by altering second mess enger levels, most notably by inhibiting phosphodiesterases that hydrolyse cyclic nucleotides. When stimulated, G proteins undergo a cycle of activati on and deactivation in which the a-subunits and the py-dimers sequentially expose binding sites for their reaction partners (receptors, guanine nucleo tides and effecters, as well as regulatory proteins). These domains can be blocked by inhibitors and this produces effects that cannot be achieved by receptor antagonists. Here, the structural and mechanistic information on G protein antagonists is summarized and an outline of the arguments supporti ng the hypothesis that G proteins per se are also potential drug targets is provided.