Dopamine-D2S receptor inhibition of calcium influx, adenylyl cyclase, and mitogen-activated protein kinase in pituitary cells:: Distinct Gα and Gβγ requirements

被引:31
作者
Banihashemi, B
Albert, PR
机构
[1] Univ Ottawa, Ottawa Hlth Res Inst, Dept Med, Ottawa, ON K1H 8M5, Canada
[2] Univ Ottawa, Ottawa Hlth Res Inst, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada
关键词
D O I
10.1210/me.2001-0220
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-mediated p42/p44 MAPK phosphorylation. These actions were blocked by pretreatment with pertussis toxin (PTX), indicating mediation by G(i/o). proteins. D2S stimulation also decreased TRH-induced MAPK/ERK kinase 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 Galpha mutants. Inhibition of adenylyl cyclase was partly rescued by Galpha(i)2 or Galpha(i)3, but Ga. alone completely reconstituted D2S-mediated inhibition of BayK8644-induced L-type calcium channel activation. Ga. and Ga,3 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 Gbetagamma signaling, only D2S-mediated inhibition of calcium influx was blocked, but not inhibition of adenylyl cyclase or MAPK. These results indicate that the dopamine-D2S receptor couples to distinct G(i/o) proteins, depending on the pathway addressed, and suggest a novel Galpha(i)3/Galpha(o)-dependent inhibition of MAPK mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase.
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收藏
页码:2393 / 2404
页数:12
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