Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors

Val J. Watts, Minh N. Vu, Brenda L. Wiens, Vera Jovanovic, Hubert H M Van Tol, Kim Neve

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The D4 dopamine receptor, a member of the D2-like dopamine receptor family, may be important in the etiology and treatment of schizophrenia. The present study was designed to examine the effects of dopamine agonist exposure on adenylate cyclase activity in HEK293 cells stably expressing recombinant-D4 receptors. Two hour pretreatment with dopamine receptor agonists resulted in heterologous sensitization of forskolin-stimulated cyclic AMP accumulation in intact cells expressing the D4.2, D4.4, or D4.7 dopamine receptor variant. The potency and efficacy of dopamine for sensitization of cyclic AMP accumulation was comparable at all D4 receptor variants. D4 dopamine receptor-mediated sensitization was blocked by the D4 antagonist, clozapine, and prevented by overnight pretreatment with pertussis toxin, implying a role for G(i)/G(o) proteins in heterologous sensitization. Further, long-term (18 h) agonist exposure resulted in a greater degree of sensitization of forskolin-stimulated cyclic AMP accumulation in both intact cells and membrane preparations of cells expressing the D4 receptor, compared to 2 h agonist exposure, without altering the density of the receptors. In addition, long-term agonist exposure decreased the abundance of G(iα) without altering the abundance of G(sα), whereas short-term agonist treatment had no effect on the immunoreactivity of either G protein. In summary, long-term agonist-induced sensitization of adenylate cyclase by the D4 receptor may involve mechanisms that do not contribute to short-term sensitization.

Original languageEnglish (US)
Pages (from-to)83-92
Number of pages10
JournalPsychopharmacology
Volume141
Issue number1
DOIs
StatePublished - 1999

Fingerprint

Dopamine D4 Receptors
Adenylyl Cyclases
Cyclic AMP
Dopamine Agonists
Colforsin
Gi-Go GTP-Binding Protein alpha Subunits
Dopamine D2 Receptors
Clozapine
HEK293 Cells
Pertussis Toxin
Dopamine Receptors
GTP-Binding Proteins
Dopamine
Schizophrenia
Cell Membrane

Keywords

  • Adenylate cyclase
  • Dopamine D receptor
  • Heterologous sensitization

ASJC Scopus subject areas

  • Pharmacology

Cite this

Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors. / Watts, Val J.; Vu, Minh N.; Wiens, Brenda L.; Jovanovic, Vera; Van Tol, Hubert H M; Neve, Kim.

In: Psychopharmacology, Vol. 141, No. 1, 1999, p. 83-92.

Research output: Contribution to journalArticle

Watts, Val J. ; Vu, Minh N. ; Wiens, Brenda L. ; Jovanovic, Vera ; Van Tol, Hubert H M ; Neve, Kim. / Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors. In: Psychopharmacology. 1999 ; Vol. 141, No. 1. pp. 83-92.
@article{d483a5a4b96246aeb5bfb7ac2afbdd56,
title = "Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors",
abstract = "The D4 dopamine receptor, a member of the D2-like dopamine receptor family, may be important in the etiology and treatment of schizophrenia. The present study was designed to examine the effects of dopamine agonist exposure on adenylate cyclase activity in HEK293 cells stably expressing recombinant-D4 receptors. Two hour pretreatment with dopamine receptor agonists resulted in heterologous sensitization of forskolin-stimulated cyclic AMP accumulation in intact cells expressing the D4.2, D4.4, or D4.7 dopamine receptor variant. The potency and efficacy of dopamine for sensitization of cyclic AMP accumulation was comparable at all D4 receptor variants. D4 dopamine receptor-mediated sensitization was blocked by the D4 antagonist, clozapine, and prevented by overnight pretreatment with pertussis toxin, implying a role for G(i)/G(o) proteins in heterologous sensitization. Further, long-term (18 h) agonist exposure resulted in a greater degree of sensitization of forskolin-stimulated cyclic AMP accumulation in both intact cells and membrane preparations of cells expressing the D4 receptor, compared to 2 h agonist exposure, without altering the density of the receptors. In addition, long-term agonist exposure decreased the abundance of G(iα) without altering the abundance of G(sα), whereas short-term agonist treatment had no effect on the immunoreactivity of either G protein. In summary, long-term agonist-induced sensitization of adenylate cyclase by the D4 receptor may involve mechanisms that do not contribute to short-term sensitization.",
keywords = "Adenylate cyclase, Dopamine D receptor, Heterologous sensitization",
author = "Watts, {Val J.} and Vu, {Minh N.} and Wiens, {Brenda L.} and Vera Jovanovic and {Van Tol}, {Hubert H M} and Kim Neve",
year = "1999",
doi = "10.1007/s002130050810",
language = "English (US)",
volume = "141",
pages = "83--92",
journal = "Psychopharmacology",
issn = "0033-3158",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors

AU - Watts, Val J.

AU - Vu, Minh N.

AU - Wiens, Brenda L.

AU - Jovanovic, Vera

AU - Van Tol, Hubert H M

AU - Neve, Kim

PY - 1999

Y1 - 1999

N2 - The D4 dopamine receptor, a member of the D2-like dopamine receptor family, may be important in the etiology and treatment of schizophrenia. The present study was designed to examine the effects of dopamine agonist exposure on adenylate cyclase activity in HEK293 cells stably expressing recombinant-D4 receptors. Two hour pretreatment with dopamine receptor agonists resulted in heterologous sensitization of forskolin-stimulated cyclic AMP accumulation in intact cells expressing the D4.2, D4.4, or D4.7 dopamine receptor variant. The potency and efficacy of dopamine for sensitization of cyclic AMP accumulation was comparable at all D4 receptor variants. D4 dopamine receptor-mediated sensitization was blocked by the D4 antagonist, clozapine, and prevented by overnight pretreatment with pertussis toxin, implying a role for G(i)/G(o) proteins in heterologous sensitization. Further, long-term (18 h) agonist exposure resulted in a greater degree of sensitization of forskolin-stimulated cyclic AMP accumulation in both intact cells and membrane preparations of cells expressing the D4 receptor, compared to 2 h agonist exposure, without altering the density of the receptors. In addition, long-term agonist exposure decreased the abundance of G(iα) without altering the abundance of G(sα), whereas short-term agonist treatment had no effect on the immunoreactivity of either G protein. In summary, long-term agonist-induced sensitization of adenylate cyclase by the D4 receptor may involve mechanisms that do not contribute to short-term sensitization.

AB - The D4 dopamine receptor, a member of the D2-like dopamine receptor family, may be important in the etiology and treatment of schizophrenia. The present study was designed to examine the effects of dopamine agonist exposure on adenylate cyclase activity in HEK293 cells stably expressing recombinant-D4 receptors. Two hour pretreatment with dopamine receptor agonists resulted in heterologous sensitization of forskolin-stimulated cyclic AMP accumulation in intact cells expressing the D4.2, D4.4, or D4.7 dopamine receptor variant. The potency and efficacy of dopamine for sensitization of cyclic AMP accumulation was comparable at all D4 receptor variants. D4 dopamine receptor-mediated sensitization was blocked by the D4 antagonist, clozapine, and prevented by overnight pretreatment with pertussis toxin, implying a role for G(i)/G(o) proteins in heterologous sensitization. Further, long-term (18 h) agonist exposure resulted in a greater degree of sensitization of forskolin-stimulated cyclic AMP accumulation in both intact cells and membrane preparations of cells expressing the D4 receptor, compared to 2 h agonist exposure, without altering the density of the receptors. In addition, long-term agonist exposure decreased the abundance of G(iα) without altering the abundance of G(sα), whereas short-term agonist treatment had no effect on the immunoreactivity of either G protein. In summary, long-term agonist-induced sensitization of adenylate cyclase by the D4 receptor may involve mechanisms that do not contribute to short-term sensitization.

KW - Adenylate cyclase

KW - Dopamine D receptor

KW - Heterologous sensitization

UR - http://www.scopus.com/inward/record.url?scp=0032928565&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032928565&partnerID=8YFLogxK

U2 - 10.1007/s002130050810

DO - 10.1007/s002130050810

M3 - Article

C2 - 9952069

AN - SCOPUS:0032928565

VL - 141

SP - 83

EP - 92

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 1

ER -