title: Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.
abstract: OBJECTIVE
  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 (Gβ5) and negatively regulate signaling downstream from monoamine GPCRs may play a role in controlling hyperactivity.
  
  
  METHODS
  To test this hypothesis, we conducted behavioral, pharmacological, and neurochemical studies using a genetic mouse model that lacked Gβ5, a subunit essential for the expression of the entire R7 RGS family.
  
  
  RESULTS
  Elimination of Gβ5-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 Gβ5-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 Gβ5-RGS-deficient mice.
  
  
  CONCLUSIONS
  These findings establish that Gβ5-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.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Xie
authors.forename: Shencheng
authors.initials: S
authors.lastname: Ge
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Collins
authors.forename: Christy L
authors.initials: CL
authors.lastname: Haynes
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Renner
authors.forename: Robert L
authors.initials: RL
authors.lastname: Meisel
authors.forename: Rafael
authors.initials: R
authors.lastname: Lujan
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
mesh_terms: D000818:Animals; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011595:Psychomotor Agitation / Q000378:metabolism* / Q000523:psychology; D020710:RGS Proteins / Q000172:deficiency*; D015398:Signal Transduction
chemical_list: D044387:GTP-Binding Protein beta Subunits; C094668:Gnb5 protein, mouse; D018377:Neurotransmitter Agents; D020710:RGS Proteins