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The complex of G protein regulator RGS9-2 and G beta(5) controls sensitization and signaling kinetics of type 5 adenylyl cyclase in the striatum

Academic Article
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Overview

authors

  • Xie, K. Q.
  • Masuho, I.
  • Brand, C.
  • Dessauer, C. W.
  • Martemyanov, Kirill

publication date

  • 2012

journal

  • Science Signaling  Journal

abstract

  • Multiple neurotransmitter systems in the striatum converge to regulate the excitability of striatal neurons by activating several heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) that signal to the type 5 adenylyl cyclase (AC5), the key effector enzyme that produces the intracellular second messenger cyclic adenosine monophosphate (cAMP). Plasticity of cAMP signaling in the striatum is thought to play an essential role in the development of drug addiction. We showed that the complex of the ninth regulator of G protein signaling (RGS9-2) with the G protein β subunit (Gβ(5)) critically controlled signaling from dopamine and opioid GPCRs to AC5 in the striatum. RGS9-2/Gβ(5) directly interacted with and suppressed the basal activity of AC5. In addition, the RGS9-2/Gβ(5) complex attenuated the stimulatory action of Gβγ on AC5 by facilitating the GTPase (guanosine triphosphatase) activity of Gα(o), thus promoting the formation of the inactive heterotrimer and inhibiting Gβγ. Furthermore, by increasing the deactivation rate of Gα(i), RGS9-2/Gβ(5) facilitated the recovery of AC5 from inhibition. Mice lacking RGS9 showed increased cAMP production and, upon withdrawal from opioid administration, enhanced sensitization of AC5. Our findings establish RGS9-2/Gβ(5) complexes as regulators of three key aspects of cAMP signaling: basal activity, sensitization, and temporal kinetics of AC5, thus highlighting the role of this complex in regulating both inhibitory and stimulatory GPCRs that shape cAMP signaling in the striatum.

subject areas

  • Adenylyl Cyclases
  • Animals
  • Blotting, Western
  • Corpus Striatum
  • Cyclic AMP
  • Fluorescence Resonance Energy Transfer
  • GTP-Binding Protein beta Subunits
  • Immunoprecipitation
  • Kinetics
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes
  • Opioid-Related Disorders
  • RGS Proteins
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • Signal Transduction
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Identity

PubMed Central ID

  • PMC3580943

International Standard Serial Number (ISSN)

  • 1937-9145

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2002922

PubMed ID

  • 22932702
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Additional Document Info

start page

  • ra63

volume

  • 5

issue

  • 239

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