NGF and BDNF elevate cAMP and IP3 levels in membranes of PC12 cells within a subsecond time period. The cAMP formation induced by NGF and BDNF pretreatment for 2 s was reduced by GDP-beta-S and PTX, but not the trk(NGFR) inhibitor K 252a. NGF, but not BDNF, induced IP3 formation. IP3 formation was reduced by K 252a, but not by GDP-beta-S and PTX. Using p75NGFR expressing, but trk(NGFR)-deficient PCNA cell membranes, NGF and BDNF induced cAMP formation, but not IP, formation. We suggest that NGF and BDNF induced cAMP formation is mediated via a p75 NGFR/G-protein mediated mechanism, and IP3 formation via a K 252a sensitive pathway.