Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptides Stimulate Mitogen-Activated Protein Kinase in the Pituitary Cell Line GH4C1 by a 3′,5′-Cyclic Adenosine Monophosphate Pathway

Abstract

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP38) regulate anterior pituitary cell secretion and proliferation. In the somatolactotrope GH4C1 cell line, these effects are mediated through the type-II-like PACAP receptor (VPAC2) coupled to the cAMP pathway. In this study, the control of the extracellularly responsive kinases (ERKs) by VIP and PACAP38 was investigated in GH4C1 cells. VIP and PACAP38 increased ERK1 and ERK2 phosphorylation and were equipotent stimulators of both kinases. ERK activation was mimicked by cholera toxin, forskolin and 8bromo-cAMP. VIP and PACAP38 activation of ERK2 was blocked by the protein kinase A inhibitor H89, whereas the protein kinase C inhibitor GF109203X, or prior PMA-induced depletion of the protein kinases C, failed to inhibit VIP and PACAP38 activation of ERK2. In contrast, thyrotropin-releasing hormone (TRH) elicited ERK activation by a PKC-dependent process. ERK activation by VIP or PACAP38 and TRH were additive and both sensitive to the MEK inhibitors PD98059 and U0126. In parallel, U0126 reduced prolactin (PRL) mRNA levels induced by VIP. These results demonstrate for the first time that VIP and PACAP38 activate ERK in GH4C1 cells. Cyclic AMP increase is sufficient to elicit ERK activation in these cells and thus likely to represent the transduction pathway underlying VIP- and PACAP38-dependent ERK activation. This mechanism seems to be involved in VIP-induced PRL gene regulation.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…The increase of PRL mRNA level induced by PACAP is mediated through a cAMP/PKA/ERK-dependent pathway that is distinct from the mechanisms involved for PRL and GH secretion (Coleman and Bancroft, 1993;Murakami et al, 1995;Koshimura et al, 1997;Yonehara et al, 2001). Similar mechanisms have been reported with the somatolactotrope GH4C1 cell line, in which PACAP activates PRL gene expression through VPAC2-R in a cAMP/PKA/ERK/Rap1-dependent manner (Le Péchon-Vallée et al, 2000;Romano et al, 2003). In the corticotrope AtT20 cell line, PACAP mimics the effect of CRH; i.e., it stimulates AC activity and triggers both POMC gene transcription and adrenocorticotropin release Lutz-Bucher, 1992a, 1995;Boutillier et al, 1994;Braas et al, 1994;Aoki et al, 1997).…”

Activation of Go-coupled Dopamine D2 Receptors Inhibits ERK1/ERK2 in Pituitary Cells

“…This finding complements studies on the stimulatory control of prolactin, showing that ERK1/2 serves as an integrative node for diverse upstream signals including G s - (36) and G q -coupled receptors (9), receptor tyrosine kinases that activate ras-dependent (24) or -independent (7) pathways, and even steroid hormones (10). Consistent with its inhibitory role in vivo, hypothalamic dopamine may reduce levels of activated ERKs to antagonize this stimulation or suppress basal prolactin gene transcription, which may be maintained in part by local pituitary-derived signals.…”

MAP kinase 1/2 (Erk 1/2) and serine/threonine specific protein kinase Akt/PKB expression and activity in the human corpus cavernosum

“…Additionally, it should be stressed that our study shows the expression or distribution of the kinases, but only the basal functional status. Further studies are MAP kinase 1=2 and serine=threonine kinase F Sommer et al necessary to show if transmitters involved in eNOSmediated penile erection, such as acetylcholine and VIP, which are also shown as activators of Akt=PKB kinases and MAP kinase 1=2 (Erk 1=2), 13,14,28 modulate eNOS activity by means of these kinases.…”