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 G(i) activities. Here, we found melittin inhibited guanine nucleotide-dependent adenylyl cyclase activity in synaptic membranes of the I at cerebral cortex. However, in insect cell membranes overexpressing specific heterotrimeric Cr proteins using baculovirus expression system, melittin showed unique effects different from those by mastoparan on G protein activities. This peptide markedly stimulated G(i1) and G(11) activities, whereas it did inhibit G(s) activities. Kinetic studies revealed that the inhibition of G(s) 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 (G(s)) activity, and both mechanisms through the stimulation of G(i) and inhibition of G(s) might be involved in the melittin-induced inhibition of adenylyl cyclase. (C) 1998 Elsevier Science Inc.