MELITTIN, A METABOSTATIC PEPTIDE INHIBITING G(S) ACTIVITY

Some basic amphiphilic peptides are known to directly stimulate hetero trimeric GTP-binding proteins (G proteins). Mastoparan and melittin ar e known to stimulate G(i) activities. Here, we found melittin inhibite d guanine nucleotide-dependent adenylyl cyclase activity in synaptic m embranes of the I at cerebral cortex. However, in insect cell membrane s overexpressing specific heterotrimeric Cr proteins using baculovirus expression system, melittin showed unique effects different from thos e by mastoparan on G protein activities. This peptide markedly stimula ted G(i1) and G(11) activities, whereas it did inhibit G(s) activities . Kinetic studies revealed that the inhibition of G(s) activity by mel ittin is attributed to the inhibition of GDP release in exchange for a dded guanine nucleotides (or the association of guanine nucleotides). Thus. melittin may be the first metabostatic peptide inhibiting G prot ein (G(s)) activity, and both mechanisms through the stimulation of G( i) and inhibition of G(s) might be involved in the melittin-induced in hibition of adenylyl cyclase. (C) 1998 Elsevier Science Inc.