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

In pituitary lactotrophs the prolactin gene is stimulated by neuropeptides and estrogen and is suppressed by dopamine via D2-type receptors. Stimulatory signals converge on activation of the mitogen-activated protein kinases ERK1/2, but dopamine regulation of this pathway is not well defined. Paradoxically, D2 agonists activate ERK1/2 in many cell types. Here we show that in prolactin-secreting GH4ZR7 cells and primary pituitary cells, dopamine treatment leads to a rapid, pronounced, and specific decrease in activated ERK1/2. The response is blocked by D2-specific antagonists and pertussis toxin. Interestingly, in stable lines expressing specific pertussis toxin-resistant Gα subunits, toxin treatment blocks dopamine suppression of MAPK in Gαi2- but not Gαo-expressing cells, demonstrating that Go-dependent pathways can effect the inhibitory MAPK response. At the nuclear level, the MEK1 inhibitor U0126 mimics the D2-agonist bromocryptine in suppressing levels of endogenous prolactin transcripts. Moreover, a good correlation is seen between the IC50 values for inhibition of MEK1 and suppression of prolactin promoter function (PD184352 > U0126 > U0125). Both dopamine and U0126 enhance the nuclear localization of ERF, a MAPK-sensitive ETS repressor that inhibits prolactin promoter activity. In addition, U0126 suppression is transferred by tandem copies of the Pit-1-binding site, consistent with mapping experiments for dopamine responsiveness. Our data suggest that ERK1/2 suppression is an obligatory step in the dopaminergic control of prolactin gene transcription and that bidirectional control of ERK1/2 function in the pituitary may provide a key mechanism for endocrine gene control. In pituitary lactotrophs the prolactin gene is stimulated by neuropeptides and estrogen and is suppressed by dopamine via D2-type receptors. Stimulatory signals converge on activation of the mitogen-activated protein kinases ERK1/2, but dopamine regulation of this pathway is not well defined. Paradoxically, D2 agonists activate ERK1/2 in many cell types. Here we show that in prolactin-secreting GH4ZR7 cells and primary pituitary cells, dopamine treatment leads to a rapid, pronounced, and specific decrease in activated ERK1/2. The response is blocked by D2-specific antagonists and pertussis toxin. Interestingly, in stable lines expressing specific pertussis toxin-resistant Gα subunits, toxin treatment blocks dopamine suppression of MAPK in Gαi2- but not Gαo-expressing cells, demonstrating that Go-dependent pathways can effect the inhibitory MAPK response. At the nuclear level, the MEK1 inhibitor U0126 mimics the D2-agonist bromocryptine in suppressing levels of endogenous prolactin transcripts. Moreover, a good correlation is seen between the IC50 values for inhibition of MEK1 and suppression of prolactin promoter function (PD184352 > U0126 > U0125). Both dopamine and U0126 enhance the nuclear localization of ERF, a MAPK-sensitive ETS repressor that inhibits prolactin promoter activity. In addition, U0126 suppression is transferred by tandem copies of the Pit-1-binding site, consistent with mapping experiments for dopamine responsiveness. Our data suggest that ERK1/2 suppression is an obligatory step in the dopaminergic control of prolactin gene transcription and that bidirectional control of ERK1/2 function in the pituitary may provide a key mechanism for endocrine gene control. D2-type receptors extracellular signal-regulated kinase mitogen-activated protein kinase mitogen-activated protein kinase kinase thyrotropin-releasing hormone green fluorescence protein prolactin growth hormone Tris-buffered saline dopamine ETS-2 repressor factor beta-adrenergic receptor kinase rous sarcoma virus Dopaminergic activation of G-protein-coupled D2-type receptors (D2R)1 regulates a range of behavioral and locomotor functions in the brain and leads to tonic inhibition of prolactin synthesis and release from the anterior pituitary. Hyperprolactinemia is observed in mice with a targeted disruption of the D2R gene along with the hypertrophic expansion of the pituitary lactotroph population and formation of pituitary adenomas in older animals (1Kelly M.A. Rubinstein M. Asa S.L. Zhang G. Saez C. Bunzow J.R. Allen R.G. Hnasko R. Ben-Jonathan N. Grandy D.K. Low M.J. Neuron. 1997; 19: 103-113Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar, 2Saiardi A. Bozzi Y. Baik J.H. Borrelli E. Neuron. 1997; 19: 115-126Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 3Asa S.L. Kelly M.A. Grandy D.K. Low M.J. Endocrinology. 1999; 140: 5348-5355Crossref PubMed Google Scholar). Inhibition of prolactin synthesis by dopamine occurs at the transcriptional level (4Maurer R.A. Nature. 1981; 294: 94-97Crossref PubMed Scopus (194) Google Scholar) and is dependent on the proximal promoter region of the prolactin gene (5Elsholtz H.P. Lew A.M. Albert P.R. Sundmark V.C. J. Biol. Chem. 1991; 266: 22919-22925Abstract Full Text PDF PubMed Google Scholar, 6McChesney R. Sealfon S.C. Tsutsumi M. Dong K.W. Roberts J.L. Bancroft C. Mol. Cell. Endocrinol. 1991; 79: R1-R7Crossref PubMed Scopus (24) Google Scholar). This region also confers transactivation by multiple stimulatory pathways, including those involving cAMP/protein kinase A, calcium, phospholipases, protein kinase C, and MAPKs. It is generally held that by antagonizing the elevation of intracellular cAMP or calcium, D2R signaling may inhibit the transactivation functions of factors like Pit-1, ETS-domain proteins, or specific transcription co-activators. Although activation of MAPK cascades are known to have an important role in mediating stimulatory responses of the prolactin gene to growth factors (7Schweppe R.E. Frazer-Abel A.A. Gutierrez-Hartmann A. Bradford A.P. J. Biol. Chem. 1997; 272: 30852-30859Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 8Castillo A.I. Tolon R.M. Aranda A. Oncogene. 1998; 16: 1981-1991Crossref PubMed Scopus (43) Google Scholar), thyrotropin-releasing hormone (TRH) (9Wang Y.H. Maurer R.A. Mol Endocrinol. 1999; 13: 1094-1104Crossref PubMed Scopus (53) Google Scholar), and even estrogen (10Watters J.J. Chun T.Y. Kim Y.N. Bertics P.J. Gorski J. Mol Endocrinol. 2000; 14: 1872-1881Crossref PubMed Scopus (108) Google Scholar), the role of MAPK regulation in the dopaminergic suppression of prolactin has not been defined. Indeed, D2R stimulation activates MAPKs in a wide range of cultured cells, including COS (11Faure M. Voyno-Yasenetskaya T.A. Bourne H.R. J. Biol. Chem. 1994; 269: 7851-7854Abstract Full Text PDF PubMed Google Scholar), Balb-c/3T3 (12Ghahremani M.H. Forget C. Albert P.R. Mol. Cell. Biol. 2000; 20: 1497-1506Crossref PubMed Scopus (41) Google Scholar), Chinese hamster ovary (13Oak J.N. Lavine N. van Tol H.H. Mol. Pharmacol. 2001; 60: 92-103Crossref PubMed Scopus (116) Google Scholar), C6 glioma (14Luo Y. Kokkonen G.C. Wang X. Neve K.A. Roth G.S. J. Neurochem. 1998; 71: 980-990Crossref PubMed Scopus (94) Google Scholar), and tissues (e.g. brain slices (15Yan Z. Feng J. Fienberg A.A. Greengard P. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11607-11612Crossref PubMed Scopus (189) Google Scholar, 16Calabresi P. Gubellini P. Picconi B. Centonze D. Pisani A. Bonsi P. Greengard P. Hipskind R.A. Borrelli E. Bernardi G. J. Neurosci. 2001; 21: 5110-5120Crossref PubMed Google Scholar) and lung epithelium (17Guerrero C. Lecuona E. Pesce L. Ridge K.M. Sznajder J.I. Am. J. Physiol. Lung Cell Mol. Physiol. 2001; 281: L79-L85Crossref PubMed Google Scholar)). This activation is generally blocked by the ADP-ribosylating agent pertussis toxin (12Ghahremani M.H. Forget C. Albert P.R. Mol. Cell. Biol. 2000; 20: 1497-1506Crossref PubMed Scopus (41) Google Scholar, 13Oak J.N. Lavine N. van Tol H.H. Mol. Pharmacol. 2001; 60: 92-103Crossref PubMed Scopus (116) Google Scholar, 14Luo Y. Kokkonen G.C. Wang X. Neve K.A. Roth G.S. J. Neurochem. 1998; 71: 980-990Crossref PubMed Scopus (94) Google Scholar), indicating a requirement for heterotrimeric Gi/o-type proteins, and in some cases by the C-terminal sequence of βARK kinase (12Ghahremani M.H. Forget C. Albert P.R. Mol. Cell. Biol. 2000; 20: 1497-1506Crossref PubMed Scopus (41) Google Scholar) or Gα subunit of retinal transducin (11Faure M. Voyno-Yasenetskaya T.A. Bourne H.R. J. Biol. Chem. 1994; 269: 7851-7854Abstract Full Text PDF PubMed Google Scholar), consistent with a role for Gβ/γ subunit dimers in stimulatory D2R signaling. Because a stimulatory effect of D2R agonists on MAPKs appears inconsistent with their inhibitory actions on prolactin gene transcription, we examined how D2R activation alters MAPK function in prolactin-secreting cells. We show here that in the pituitary cell line GH4ZR7, dopamine treatment lowers constitutive and hormone-stimulated levels of activated MAPKs, ERK1 and ERK2. The inhibitory response is rapid and dependent on specific heterotrimeric G-proteins and specific MAPK types in that p38 MAPKs are not regulated in a similar manner to ERKs. The effects of MAPKK (MEK1) inhibitors on prolactin transcription parallel those of dopamine and are dependent in part on Pit-1 and ETS-type transcription factors. Finally, dopaminergic inhibition of ERK function is not restricted to transformed pituitary cell lines but is observed also in normal primary pituicytes, suggesting a physiological role for this regulatory mechanism. MEK1 inhibitors PD98059, PD184352, U0126, U0125, and pertussis toxin were purchased fromCalbiochem. Dopamine, bromocryptine, sulpiride, spiperone, and sorbitol were from Sigma. TRH was from Roche Molecular Biochemicals. The luciferase reporter plasmid −422 rPRL-Luc, rGH-Luc, RSV-Luc, 3x1P-Luc, and 3xSp1-Luc constructs were described previously (5Elsholtz H.P. Lew A.M. Albert P.R. Sundmark V.C. J. Biol. Chem. 1991; 266: 22919-22925Abstract Full Text PDF PubMed Google Scholar, 18Lew A.M. Yao H. Elsholtz H.P. J. Biol. Chem. 1994; 269: 12007-12013Abstract Full Text PDF PubMed Google Scholar). GFP-ERF fusion protein expression vector was prepared by in-frame insertion of the ERF cDNA sequence into pEGFP-C1 (CLONTECH). GH4ZR7 cells were maintained in Ham's F-10 with 12.5% horse serum and 2.5% fetal calf serum. Transfections were done as previously described (18Lew A.M. Yao H. Elsholtz H.P. J. Biol. Chem. 1994; 269: 12007-12013Abstract Full Text PDF PubMed Google Scholar). For primary culture, the pituitaries were isolated from 3-month-old Sprague-Dawley rats, washed with ice-cold phosphate-buffered saline and Dulbecco's modified Eagle's medium, and resuspended in defined medium (Dulbecco's modified Eagle's medium, penicillin/streptomycin, 30 μg/ml putrescine, 1 μm hydrocortisone, 5 μg/ml insulin, 5 μg/ml transferrin, 0.375% bovine serum albumin, and 10 pm T3). The cells were separated mechanically by passing progressively through a Pasteur pipette, 18- and 23-gauge needles. Dispersed cells were plated onto poly-l-lysine-coated culture plates and incubated in defined media for 48 h before treatments. Pertussis toxin-insensitive Gαi/o mutants containing C-terminal Cys to Ser substitutions and cloned into expression vector pcDNA3 (Invitrogen) were kindly provided by Dr. Paul Albert, University of Ottawa) (12Ghahremani M.H. Forget C. Albert P.R. Mol. Cell. Biol. 2000; 20: 1497-1506Crossref PubMed Scopus (41) Google Scholar). GH4ZR7 cells were co-transfected with the mutant Gαi/o subunit constructs and pcDNA3.1/hygromycin vector using electroporation (500 μfarad capacitance, 280 volts) and cultured in Ham's F-10 medium (12.5% horse serum, 2.5% fetal bovine serum) containing 300 μg/ml hygromycin-B for 3–4 weeks. Antibiotic-resistant clones were picked (25 clones/transfection) and tested for expression of recombinant Gαi/o RNA transcripts using 32P-labeled probes that recognized 3′ non-coding sequences specific to the vector. Transcript-positive clones were assessed by Western blot for the presence of corresponding Gαi/o proteins. mRNA from GH4ZR7 cells was prepared using oligo-dT cellulose (Collaborative Biomedical Tech.). Blots were probed with random primer labeled ([32P]dATP) cDNAs for Gαi2, Gαo, PRL, GH, or tubulin as previously described (26Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar). Cells from 6-cm dishes were harvested in 0.2 ml of radioimmune precipitation assay buffer, extract protein was quantified by BCA protein assay (Pierce, Rockford, IL), samples were resolved on SDS 12% polyacrylamide gels at 100 V, and proteins were transferred to nitrocellulose. Blots were incubated for 2 h in 5% nonfat dry milk in 1× TBS. The blots were then incubated overnight with primary antibody in fresh 5% nonfat dry milk in 1× TBS followed by a 1-h incubation with horseradish peroxidase-conjugated secondary antibody at room temperature. The peroxidase was and to ETS of the prolactin promoter were by using the of M. J. J. B. PubMed Scopus Google Scholar). a primer specific for the or of the prolactin promoter and an ETS and The was in a to a The was and and into the vector. to ERK1/2, and were to MAPK by Western ERK1/2 was using the from Cell was done with GH4ZR7 cell extract using The was washed and in kinase with protein as The level of ERK was by in Western blot using GH4ZR7 cells were with GFP-ERF expression vector and plated on with the cells were washed and in were prepared by the cells with in phosphate-buffered saline and examined by GFP-ERF proteins were using an at of MAPKs in GH4ZR7 cells was by the activated of the and by the of MAPKs to the ETS that activated ERK1 and are and at in GH4ZR7 cells cultured in or medium for even of the This level of activated may from stimulatory factors from pituitary cells, as by a of in levels by serum but to control by h cells in a similar manner in levels the regulation of was examined and in the presence of ERK as the In were suppressed by of cells to dopamine This suppression was observed at dopamine previously to inhibit prolactin gene transcription (5Elsholtz H.P. Lew A.M. Albert P.R. Sundmark V.C. J. Biol. Chem. 1991; 266: 22919-22925Abstract Full Text PDF PubMed Google Scholar, 18Lew A.M. Yao H. Elsholtz H.P. J. Biol. Chem. 1994; 269: 12007-12013Abstract Full Text PDF PubMed Google Scholar), and was blocked by and 2 and data not In to ERK1/2, the was not by dopamine 2 demonstrating in the MAPK response to D2R activation in GH4ZR7 cells. the cell for dopaminergic suppression of ERK1/2, we the dopamine response in normal pituitary cells. Dispersed primary were prepared in defined medium and with D2 agonists and using GH4ZR7 cells. In experiments of similar dopamine or bromocryptine levels by demonstrating that regulation of MAPK in normal the response in the GH4ZR7 suppression of by dopamine specific we examined the of this response to pertussis toxin. of GH4ZR7 cells with pertussis toxin effect on the level of or on stimulation of ERK1/2 by signals via but suppression of ERK1/2 of a response. of the of to by pertussis a to proteins are for to specific signaling We stable GH4ZR7 clones that pertussis toxin-resistant of and and examined Gα was for inhibition of ERK1/2. RNA using probes specific for the of recombinant Gα with data in cloned lines that the mutant Gα pertussis toxin and dopamine addition, cells to suppression of ERK1/2 function by dopamine was In pertussis toxin was in dopamine regulation of levels in cells indicating that this Gα may in D2R activation to MAPK D2R activation in lactotrophs signaling that may prolactin including a in cAMP inhibition of and a decrease in Because dopamine ERK1/2 function in GH4ZR7 cells and primary pituitary cells, we the of this regulatory mechanism on expression of the endogenous prolactin that similar to bromocryptine, MEK1 inhibitors U0126 and a in prolactin RNA transcripts a of the growth hormone gene and tubulin control were in response to the treatments. The U0126 is a inhibitor of MEK1 the and also a inhibitor of the endogenous prolactin gene at 48 a between ERK1/2 suppression and in prolactin gene transcription, we the of MEK1 inhibitors a wide range of IC50 values for the suppression of ERK1/2 activation to prolactin promoter is a range in the of PD184352, U0126, and to inhibit the prolactin in good with the range and of to ERK1/2 activation > U0126 > U0125). Moreover, the of MEK1 inhibitors for the prolactin promoter is by the promoter (5Elsholtz H.P. Lew A.M. Albert P.R. Sundmark V.C. J. Biol. Chem. 1991; 266: 22919-22925Abstract Full Text PDF PubMed Google Scholar), was by even the MEK1 inhibitors and at 100 μm We have previously that ERF, a transcriptional repressor of the ETS-domain can inhibit the prolactin gene promoter by at and Pit-1 J. Sundmark M. D. Elsholtz H.P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In ERF is a for MAPK M.A. J. 14: PubMed Scopus Google Scholar), and MAPK activation of the repressor from L. D. G. G. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar), an mechanism for of gene We examined by a in ERK1/2 function in or GH4ZR7 cells the of In cells, a GFP-ERF fusion protein was from with a control of cells to dopamine or U0126 a of GFP-ERF to effect on the of in control that ERF sequences were for nuclear of localization data that nuclear GFP-ERF was in of cells, in to in cells nuclear localization of GFP-ERF to The promoter region of the prolactin gene and that have been to at and A.P. Gutierrez-Hartmann A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Maurer R.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We the of ETS in a prolactin ETS at 3′ to the Pit-1-binding was also in dopamine and U0126 of the prolactin promoter by and a in to dopamine and the MEK1 inhibitor was not seen of ETS of the prolactin We have that a Pit-1-binding to is to dopamine inhibition to a (e.g. are not regulated by dopamine (5Elsholtz H.P. Lew A.M. Albert P.R. Sundmark V.C. J. Biol. Chem. 1991; 266: 22919-22925Abstract Full Text PDF PubMed Google Scholar). Interestingly, as in U0126 also inhibits of a promoter but not a demonstrating that dopamine signaling at the nuclear level in GH4ZR7 cells may of the ERK1/2 with a role for Pit-1 in inhibition by U0126, we that the growth hormone promoter is also with the prolactin the of U0126 to levels of growth hormone mRNA that in a transcriptional responses to MAPK suppression may on that in the prolactin gene but not the growth hormone This that dopamine D2R signaling in normal pituitary cells and prolactin-secreting cell lines leads to a in ERK1/2 not stimulatory effects of (e.g. on ERK1/2, but also levels of activated ERK1/2 observed in of GH4ZR7 cells and primary pituitary cells. The of in an in levels is followed by a that or factors may to the levels of activated ERK in pituitary cells. may or of the growth factor that are in cells and primary as can of ERK1/2 in pituitary (7Schweppe R.E. Frazer-Abel A.A. Gutierrez-Hartmann A. Bradford A.P. J. Biol. Chem. 1997; 272: 30852-30859Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). to this using are in Although activation of ERK1/2 by including is a well in and tissues (26Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar, van K.M. 1997; PubMed Scopus Google Scholar), the mechanism of rapid inhibition of ERK1/2 by this of receptors is well In GH4ZR7 cells, dopamine inhibition of ERK1/2 inhibitory effects on or (18Lew A.M. Yao H. Elsholtz H.P. J. Biol. Chem. 1994; 269: 12007-12013Abstract Full Text PDF PubMed Google Scholar, P.R. Neve K.A. Bunzow J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, L. C. M. Albert P. Bunzow J. J. J. Biol. Chem. Full Text PDF PubMed Google Scholar), as that or can also ERK1/2 Interestingly, using Gα proteins in cells J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar) and (12Ghahremani M.H. Forget C. Albert P.R. Mol. Cell. Biol. 2000; 20: 1497-1506Crossref PubMed Scopus (41) Google Scholar) a requirement for in the inhibition of the of Gαo, but not Gαi2, to dopamine suppression of ERK1/2 that pathways of cAMP inhibition may a This may of in transcriptional inhibition of the prolactin as we have previously that a inhibits prolactin promoter function a decrease in intracellular cAMP (18Lew A.M. Yao H. Elsholtz H.P. J. Biol. Chem. 1994; 269: 12007-12013Abstract Full Text PDF PubMed Google Scholar). control of ERK1/2 by dopamine may the regulation of specific that MAPKs or or that in the signaling B. R.E. P.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar) that dopamine can a in GH4ZR7 cell an effect blocked by the and to pertussis toxin. of receptors was to the B. R.E. P.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar), suggesting in the signaling pathways by receptors in GH4ZR7 cells. the is a in ERK1/2 Inhibition of can ERK1/2 signaling in prolactin-secreting cell lines M. Mol. Endocrinol. 2001; PubMed Scopus Google Scholar) by of an in the kinase of inhibition by dopamine to a in activated ERK1/2. Moreover, a and Greengard P. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, A. H. H. M. H. Y. A. Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), has been in as a for the D2R intracellular G.S. S.L. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), a between the D2R and is at levels in cell including those in activate ERK1/2, role in dopaminergic inhibition of ERK1/2 in lactotrophs to of the prolactin gene is suppressed by MEK1 inhibitors with a for suppression of promoter function that well to the IC50 values for MEK1 Although of kinase inhibitor data is by the of is from a of multiple kinase inhibitors H. M. P. J. 2000; PubMed Scopus Google Scholar) that MEK1 inhibitors to many kinase In addition, the prolactin effects of MEK1 inhibitors tested in is that transcription by a mechanism. with the RNA blot data that ERK1/2 stimulated by or maintained at levels by pituitary may for prolactin gene and an for inhibitory control by D2R signaling The in transcriptional inhibition by dopamine and MEK1 inhibitors to of the ERF repressor to and regulation at Pit-1 of the prolactin Although in some lines the repressor is to serum the of for nuclear L. D. G. G. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar), ERF in GH4ZR7 cells is restricted to the even serum similar is seen in pituitary cells. and R. N. The of dopamine and the inhibitor U0126 to nuclear of ERF, the that inhibition of ERK1/2 is a requirement for regulation of this transcription Although data that ERF can by the of the prolactin promoter J. Sundmark M. D. Elsholtz H.P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), of this or a were to the transcriptional response to dopamine or proximal ETS may or ERF may inhibit at Pit-1 as by of the prolactin J. Sundmark M. D. Elsholtz H.P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Although the confers dopamine (5Elsholtz H.P. Lew A.M. Albert P.R. Sundmark V.C. J. Biol. Chem. 1991; 266: 22919-22925Abstract Full Text PDF PubMed Google Scholar), has not previously been a for MAPK regulation on of stimulatory signaling pathways in cells. as a for the a key role in the of transcriptional inhibition of ERK1/2 may to with a decrease in In we show that suppression of ERK1/2 by dopamine may a key role in the regulation of the prolactin This on the stimulatory control of that ERK1/2 as an for signals including C. R. A. C. 2000; PubMed Scopus Google Scholar) and receptors (9Wang Y.H. Maurer R.A. Mol Endocrinol. 1999; 13: 1094-1104Crossref PubMed Scopus (53) Google Scholar), receptor kinases that activate A.P. Gutierrez-Hartmann A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or (7Schweppe R.E. Frazer-Abel A.A. Gutierrez-Hartmann A. Bradford A.P. J. Biol. Chem. 1997; 272: 30852-30859Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar) pathways, and even (10Watters J.J. Chun T.Y. Kim Y.N. Bertics P.J. Gorski J. Mol Endocrinol. 2000; 14: 1872-1881Crossref PubMed Scopus (108) Google Scholar). with inhibitory role in dopamine may levels of activated to this stimulation or prolactin gene transcription, may maintained in part by Finally, inhibition of ERK1/2 is generally as a mechanism that an or stimulatory experiments a in some or as some receptor kinases H. J.R. J.S. J.R. E. Wang B. Cell Biol. 2001; PubMed Scopus Google Scholar), a suppression of ERK1/2 with in gene transcription or cell We and of for expression and of Paul Albert and of Ottawa) for mutant Gα expression Asa and of for pituitaries and primary culture and and of for of

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.