The D2s dopamine receptor stimulates phospholipase D activity: a novel signaling pathway for dopamine.
The D2 dopamine receptor isoforms signal to a variety of cellular effectors in both the central nervous system and periphery. Two alternative splice forms of the D2 dopamine receptor exist, the D2s (short) and D2l (long), which has an insertion of 29 amino acids in the third intracellular loop (). In cells of the anterior lobe of the pituitary, D2 dopamine receptors (both forms) are present on lactotroph cells coupled to the inhibition of adenylyl cyclase, activation of voltage-gated calcium channels, and inhibition of potassium channels. We describe here a novel signaling pathway for the D2s, which is the activation of phospholipase D (PLD). GH4C1 cells, a clonal line derived from a rat pituitary tumor, were stably transfected with the gene encoding the D2s, generating GH4-121 cells. Treatment of GH4-121 cells with a dopaminergic agonist resulted in activation of PLD in both a dose-dependent and time-dependent manner. This signaling pathway was not inhibited by prior treatment of cells with pertussis toxin at concentrations that ablate other D2s receptor signaling in this cell line. The stimulation of PLD activity by D2s appeared to correlate with the presence of a specific protein kinase C isoform, PKCepsilon. The D2s stimulation of PLD activity was blocked by preincubation of cells with C3 exoenzyme, indicating that the stimulation of PLD may involve Rho family members. The stimulation of PLD by dopaminergic agonists took place in the absence of any detectable stimulation of phosphoinositide metabolism.
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Department of Biochemistry, College of Medicine, University of Tennessee, Memphis, Tennessee 28163, USA.
D036002:ADP Ribose Transferases / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D001905:Botulinum Toxins; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004789:Enzyme Activation; D007527:Isoenzymes / Q000378:metabolism; D037342:Pertussis Toxin; D010703:Phorbol Esters / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D018491:Dopamine Agonists; D007527:Isoenzymes; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D017448:Receptors, Dopamine D2; D010566:Virulence Factors, Bordetella; D013973:Thyrotropin-Releasing Hormone; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D037342:Pertussis Toxin; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D010739:Phospholipase D; D001905:Botulinum Toxins; D004298:Dopamine