Melittin, a metabostatic peptide inhibiting Gs activity.

Some basic amphiphilic peptides are known to directly stimulate heterotrimeric GTP-binding proteins (G proteins). Mastoparan and melittin are known to stimulate Gi activities. Here, we found melittin inhibited guanine nucleotide-dependent adenylyl cyclase activity in synaptic membranes of the rat cerebral cortex. However, in insect cell membranes overexpressing specific heterotrimeric G proteins using baculovirus expression system, melittin showed unique effects different from those by mastoparan on G protein activities. This peptide markedly stimulated Gi1 and G11 activities, whereas it did inhibit Gs activities. Kinetic studies revealed that the inhibition of Gs activity by melittin is attributed to the inhibition of GDP release in exchange for added guanine nucleotides (or the association of guanine nucleotides). Thus, melittin may be the first metabostatic peptide inhibiting G protein (Gs) activity, and both mechanisms through the stimulation of Gi and inhibition of Gs might be involved in the melittin-induced inhibition of adenylyl cyclase.