The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2.
Dopamine receptors are GPCRs that play important roles in locomotion, reward, and cognitive processes. Previously, we demonstrated that this receptor transactivates PDGFRbeta to modulate ERK1/2 and NMDA receptor activity. Downregulation of maturely glycosylated PDGFRbeta by prolonged exposure to PDGF-BB eliminated PDGF-BB-mediated ERK1/2 activation. The DRD4-mediated ERK1/2 response was only partially blunted by PDGF-BB-mediated downregulation, but remained sensitive to the PDGFRbeta kinase inhibitor tyrphostin A9. Tunicamycin prevented the N-linked glycosylation and maturation of PDGFRbeta as well as its activation by PDGF-BB. However, upon tunicamycin treatment, DRD4 continued to signal to ERK1/2 in a tyrphostin A9-sensitive manner. Collectively, our observations indicate that DRD4, unlike PDGF-BB, can activate a pool of intracellularly located PDGFRbeta.
Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Robin S
RS
Gill
Marilyn S
MS
Hsiung
Chi S
CS
Sum
Natalie
N
Lavine
Stewart D
SD
Clark
Hubert H M
HH
Van Tol
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000077214:Becaplermin; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D014415:Tunicamycin / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016194:Receptors, N-Methyl-D-Aspartate; D020032:Tyrphostins; C406122:tyrphostin A9; D014415:Tunicamycin; D050638:Receptors, Dopamine D4; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3