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Submitted on September 4, 2001
Accepted on July 10, 2002
and Gß
requirements
1 Ottawa Health Research Institute, Neuroscience, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H-8M5, palbert@uottawa.ca
* To whom correspondence should be addressed. E-mail: palbert{at}uottawa.ca.
The G protein specificity of multiple signaling pathways of the dopamine-D2S (short form) receptor was investigated in GH4ZR7 lactotroph cells. Activation of the dopamine-D2S receptor inhibited forskolin-induced cAMP production, reduced BayK8644-activated calcium influx, and blocked TRH (TRH)-mediated p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation. These actions were blocked by pretreatment with pertussis toxin (PTX), indicating mediation by Gi/o proteins. D2S stimulation also decreased TRH-induced MAPK/ERK kinase (MEK1/2) phosphorylation. TRH induced c-Raf but not B-Raf activation and the D2S receptor inhibited both TRH-induced c-Raf and basal B-Raf kinase activity. After PTX treatment, D2S receptor signaling was rescued in cells stably transfected with individual PTX-insensitive G mutants. Inhibition of adenylyl cyclase was partly rescued by Gi2 or Gi3, but Go alone completely reconstituted D2S-mediated inhibition of BayK8644-induced L-type calcium channel activation. Go and Gi3 were the main components involved in D2S-mediated p42/44 MAPK inhibition. In cells transfected with the carboxyl-terminal domain of G-protein receptor kinase to inhibit Gß signaling, only D2S-mediated inhibition of calcium influx was blocked, but not inhibition of AC or MAPK. These results indicate that the dopamine-D2S receptor couples to distinct Gi/o proteins depending on the pathway addressed, and suggest a novel Gi3/Go-dependent inhibition of MAPK mediated by c-Raf and B-Raf-dependent inhibition of MEK1/2.
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