Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems
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Rationale and objectives
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.
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.
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.
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.
KeywordsAttention deficit hyperactivity disorder (ADHD) Basal ganglia Motor control Hyperactivity Synaptic transmission G protein-coupled receptors Regulators of G protein signaling (RGS)
We would like to thank Dr. Ching-Kang Jason Chen (VCU) for providing Gβ5−/− mouse line and Dr. William Simonds (NIH) for the generous gift of anti-Gβ5 antibodies. This work was supported by NIH grants DA021743 (K.A.M.), DA026405 (K.A.M.), DA019921 (K.J.R.), and DA13680 (R.L.M.); McKnight Land-Grant Professorship award (K.A.M.), NSF 0921874 (K.J.R); grants from the Spanish Ministry Science and Innovation (BFU2009-08404/BFI and CONSOLIDER-Ingenio CSD2008-00005; RL); and Searle Scholars Award (C.L.H.).
The authors declare that except for the income received from the primary employers and NIH grants listed in the “Acknowledgements” section, no financial compensation has been received from any individual or corporate entity over the past 3 years of research or professional service that could be perceived as constituting a potential conflict of interest.
- Anderson GR, Lujan R, Semenov A, Pravetoni M, Posokhova EN, Song JH, Uversky V, Chen CK, Wickman K, Martemyanov KA (2007) Expression and localization of RGS9-2/G 5/R7BP complex in vivo is set by dynamic control of its constitutive degradation by cellular cysteine proteases. J Neurosci 27:14117–14127PubMedCrossRefGoogle Scholar
- Anderson GR, Cao Y, Davidson S, Truong HV, Pravetoni M, Thomas MJ, Wickman K, Giesler GJ Jr, Martemyanov KA (2010) R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine. Neuropsychopharmacology 35:1040–1050PubMedCrossRefGoogle Scholar
- Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ, van't Slot R, Minderaa RB, Gunning WB, Pearson PL, Sinke RJ (2003) A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 72:1251–1260PubMedCrossRefGoogle Scholar
- Findling RL, McNamara NK, Stansbrey RJ, Maxhimer R, Periclou A, Mann A, Graham SM (2007) A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. J Child Adolesc Psychopharmacol 17:19–33PubMedCrossRefGoogle Scholar
- Jensen V, Rinholm JE, Johansen TJ, Medin T, Storm-Mathisen J, Sagvolden T, Hvalby O, Bergersen LH (2009) N-methyl-d-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder. Neuroscience 158:353–364PubMedCrossRefGoogle Scholar
- Kovoor A, Seyffarth P, Ebert J, Barghshoon S, Chen CK, Schwarz S, Axelrod JD, Cheyette BN, Simon MI, Lester HA, Schwarz J (2005) D2 dopamine receptors colocalize regulator of G-protein signaling 9–2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways. J Neurosci 25:2157–2165PubMedCrossRefGoogle Scholar
- Mazei-Robinson MS, Blakely RD (2006) ADHD and the dopamine transporter: are there reasons to pay attention? Handb Exp Pharmacol (175):373–415Google Scholar
- Nijmeijer JS, Arias-Vasquez A, Rommelse NN, Altink ME, Anney RJ, Asherson P, Banaschewski T, Buschgens CJ, Fliers EA, Gill M, Minderaa RB, Poustka L, Sergeant JA, Buitelaar JK, Franke B, Ebstein RP, Miranda A, Mulas F, Oades RD, Roeyers H, Rothenberger A, Sonuga-Barke EJ, Steinhausen HC, Faraone SV, Hartman CA, Hoekstra PJ (2010) Identifying loci for the overlap between attention-deficit/hyperactivity disorder and autism spectrum disorder using a genome-wide QTL linkage approach. J Am Acad Child Adolesc Psychiatry 49:675–685PubMedGoogle Scholar
- Rahman Z, Schwarz J, Gold SJ, Zachariou V, Wein MN, Choi KH, Kovoor A, Chen CK, DiLeone RJ, Schwarz SC, Selley DE, Sim-Selley LJ, Barrot M, Luedtke RR, Self D, Neve RL, Lester HA, Simon MI, Nestler EJ (2003) RGS9 modulates dopamine signaling in the basal ganglia. Neuron 38:941–952PubMedCrossRefGoogle Scholar
- Ruano D, Abecasis GR, Glaser B, Lips ES, Cornelisse LN, de Jong AP, Evans DM, Davey Smith G, Timpson NJ, Smit AB, Heutink P, Verhage M, Posthuma D (2010) Functional gene group analysis reveals a role of synaptic heterotrimeric G proteins in cognitive ability. Am J Hum Genet 86:113–125PubMedCrossRefGoogle Scholar