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.
This research output has an Altmetric Attention Score of 6. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 September 2012.
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Altmetric has tracked 32,948,899 research outputs across all sources so far. This one has received more attention than most of these and is in the 72nd percentile.
So far Altmetric has tracked 3,643 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 18.8. This one is in the 47th percentile – i.e., 47% of its peers scored the same or lower than it.
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