Pivotal role for aspartate-80 in the regulation of dopamine D2 receptor affinity for drugs and inhibition of adenylyl cyclase

Kim Neve, Barbara A. Cox, Robert A. Henningsen, Athena Spanoyannis, Rachael L. Neve

Research output: Contribution to journalArticle

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Abstract

An aspartate residue corresponding to aspartate-80 of dopamine D2 receptors is strictly conserved among receptors that couple to guanine nucleotide-binding proteins. Mutation of this residue alters the function of several classes of neurotransmitter receptors. Dopamine D2 receptors couple to the guanine nucleotide-binding protein Gi to inhibit adenylyl cyclase (ATP-pyrophosphate-lyase, cyclizing; EC 4.6.1.1). Like other Gi-coupled receptors, the binding of agonists and some antagonists to D2 receptors is sensitive to pH and sodium. In the present report, we demonstrate that substitution of an alanine or glutamate residue for aspartate-80 severely impairs inhibition of adenylyl cyclase by D2 receptors and also abolishes or decreases the regulation of the affinity of D2 receptors for agonists and substituted benzamide antagonists by sodium and pH. Our data support the hypothesis that the conformation of D2 receptors is maintained by interactions of monovalent cations with aspartate-80. The regulation of D2 receptors by this interaction has important consequences for the affinity of D2 receptors for ligands and for signal transduction by D2 receptors.

Original languageEnglish (US)
Pages (from-to)733-739
Number of pages7
JournalMolecular Pharmacology
Volume39
Issue number6
StatePublished - Jun 1991

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Dopamine D2 Receptors
Adenylyl Cyclases
Aspartic Acid
Guanine Nucleotides
Pharmaceutical Preparations
Carrier Proteins
Sodium
Monovalent Cations
Neurotransmitter Receptor
Alanine
Glutamic Acid
Signal Transduction
Ligands
Mutation

ASJC Scopus subject areas

  • Pharmacology

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Pivotal role for aspartate-80 in the regulation of dopamine D2 receptor affinity for drugs and inhibition of adenylyl cyclase. / Neve, Kim; Cox, Barbara A.; Henningsen, Robert A.; Spanoyannis, Athena; Neve, Rachael L.

In: Molecular Pharmacology, Vol. 39, No. 6, 06.1991, p. 733-739.

Research output: Contribution to journalArticle

Neve, Kim ; Cox, Barbara A. ; Henningsen, Robert A. ; Spanoyannis, Athena ; Neve, Rachael L. / Pivotal role for aspartate-80 in the regulation of dopamine D2 receptor affinity for drugs and inhibition of adenylyl cyclase. In: Molecular Pharmacology. 1991 ; Vol. 39, No. 6. pp. 733-739.
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