Gonadotropin releasing hormone (GnRH) is secreted in a pulsatile manner to stimulate the synthesis and release of the glycoprotein hormones LH and FSH from pituitary gonadotropes. GnRH is therefore regarded as the key hormone of reproduction and understanding its receptor signaling is crucial for basic and clinical applications. The role of PKC isoforms in GnRH-stimulated p38MAPK was examined in theαT3-1 and LβT2 gonadotrope cell lines. Incubation of the cells with GnRH resulted in a protracted activation of p38. By using the PKC activator,phorbol-12-myristate-13-acetate(PMA) we found that PKC is involved in the activation phase of p38 by GnRH.Gonadotropes express conventional PKCα and PKCβII, novel PKCδ, PKCε and PKCθ and atypical PKC-ι/λ.The pan PKCs inhibitor GF 109203X markedly reduced GnRH- and PMA-stimulation of p38.The use of dominant-negative plasmids for the various PKCs has revealed that PKCβand PKCδmediate p38 activation by GnRH. Furthermore, unlike the dogma that p38 is localized in the nucleus of various cells, we localized p38 to the plasma membrane. Upon activation by GnRH, we noticed blebs formation, apparent migration and relocation of p38 to the blebs. We suggest that the activated p38 may be involved in gonadotropes migration. The physiological significance of gonadotropes migration is under investigation.