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G?5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.

ABSTRACT: Our knowledge about genes involved in the control of basal motor activity that may contribute to the pathology of the hyperactivity disorders, e.g., attention deficit hyperactivity disorder (ADHD), is limited. Disruption of monoamine neurotransmitter signaling through G protein-coupled receptors (GPCR) is considered to be a major contributing factor to the etiology of the ADHD. Genetic association evidence and functional data suggest that regulators of G protein signaling proteins of the R7 family (R7 RGS) that form obligatory complexes with type 5 G protein beta subunit (G?5) and negatively regulate signaling downstream from monoamine GPCRs may play a role in controlling hyperactivity.To test this hypothesis, we conducted behavioral, pharmacological, and neurochemical studies using a genetic mouse model that lacked G?5, a subunit essential for the expression of the entire R7 RGS family.Elimination of G?5-RGS complexes led to a striking level of hyperactivity that far exceeds activity levels previously observed in animal models. This hyperactivity was accompanied by motor learning deficits and paradoxical behavioral sensitization to a novel environment. Neurochemical studies indicated that G?5-RGS-deficient mice had higher sensitivity of inhibitory GPCR signaling and deficits in basal levels, release, and reuptake of dopamine. Surprisingly, pharmacological treatment with monoamine reuptake inhibitors failed to alter hyperactivity. In contrast, blockade of NMDA receptors reversed the expression of hyperactivity in G?5-RGS-deficient mice.These findings establish that G?5-RGS complexes are critical regulators of monoamine-NMDA receptor signaling cross-talk and link these complexes to disorders that manifest as hyperactivity, impaired learning, and motor dysfunctions.

SUBMITTER: Xie K

PROVIDER: S-EPMC3260372 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.

Xie Keqiang K Ge Shencheng S Collins Victoria E VE Haynes Christy L CL Renner Kenneth J KJ Meisel Robert L RL Lujan Rafael R Martemyanov Kirill A KA

Psychopharmacology 20110716 3

<h4>Rationale and objectives</h4>Our knowledge about genes involved in the control of basal motor activity that may contribute to the pathology of the hyperactivity disorders, e.g., attention deficit hyperactivity disorder (ADHD), is limited. Disruption of monoamine neurotransmitter signaling through G protein-coupled receptors (GPCR) is considered to be a major contributing factor to the etiology of the ADHD. Genetic association evidence and functional data suggest that regulators of G protein ...[more]

PMID: 21766168

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G?5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.

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Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.

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