D2 dopamine receptor-induced sensitization of adenylyl cyclase type 1 is G alpha(s) independent

Neuropharmacology. 2006 Apr;50(5):576-84. doi: 10.1016/j.neuropharm.2005.11.004. Epub 2005 Dec 27.

Abstract

Acute activation of D2 dopamine receptors inhibits adenylyl cyclase (EC 4.6.1.1), whereas persistent activation of these inhibitory receptors results in a compensatory increase in cyclic AMP accumulation. This sensitization of adenylyl cyclase is thought to involve enhanced Galpha(s)-adenylyl cyclase interactions; however, the absolute requirement of Galpha(s) has not been determined. The present study used a Galpha(s)-deficient cell line to examine directly the role of Galpha(s) in D2 dopamine receptor-induced sensitization of recombinant adenylyl cyclase type 1 (AC1) and 5 (AC5). In acute experiments, quinpirole activation of the D2 dopamine receptor inhibited AC1 and AC5 activity, indicating that the acute regulatory properties of AC1 and AC5 were retained in the absence of Galpha(s). Subsequent experiments revealed that short-term (2 h) activation of the D2 dopamine receptor resulted in significantly enhanced forskolin-stimulated AC1 activity in the absence of Galpha(s), whereas sensitization of forskolin-stimulated AC5 activity appeared to require Galpha(s). The Galpha(s)-independent sensitization of AC1 was explored further using AC1-selective activation protocols (A23187 and CCE) following short- and long-term agonist treatment. These studies revealed that persistent activation of D2 dopamine receptors sensitized AC1 activity to Ca2+ stimulation in cells devoid of endogenous Galpha(s) and demonstrate directly that sensitization of AC1 is Galpha(s)-independent.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism*
  • Animals
  • Calcimycin / pharmacology
  • Calcium / metabolism
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacokinetics
  • Dopamine D2 Receptor Antagonists
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation / drug effects
  • GTP-Binding Protein alpha Subunits / metabolism*
  • Hybrid Cells
  • Ionophores / pharmacology
  • Isoproterenol / pharmacology
  • Mice
  • Quinpirole / pharmacology
  • RNA, Messenger / biosynthesis
  • Rabbits
  • Receptors, Dopamine D2 / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Transfection / methods
  • Tritium / pharmacokinetics

Substances

  • Dopamine D2 Receptor Antagonists
  • GTP-Binding Protein alpha Subunits
  • Ionophores
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Tritium
  • Colforsin
  • Quinpirole
  • Calcimycin
  • Cyclic AMP
  • Adenylyl Cyclases
  • adenylyl cyclase 1
  • Isoproterenol
  • Calcium