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

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Abstract

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.

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.

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Acknowledgements

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.).

Disclosure

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.

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Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA

    Keqiang Xie & Kirill A. Martemyanov

  2. Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Robert L. Meisel

  3. Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA

    Shencheng Ge & Christy L. Haynes

  4. Department of Biology, University of South Dakota, Vermillion, SD, 57069, USA

    Victoria E. Collins & Kenneth J. Renner

  5. Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02006, Albacete, Spain

    Rafael Lujan

  6. Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, 3C2, Jupiter, FL, 33458, USA

    Kirill A. Martemyanov

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  1. Keqiang Xie
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Supplemental Figure 1

Pattern of ambulatory activities of mice in the open field. Movements of mice of both genotypes were tracked in the open field chamber for 180 min. Grid represents the position of the infrared beams. Beam crossings are represented by the red lines. Red circle is the position of the mouse at the end of tracking. Please note significantly greater activity of Gβ5−/− with preservation of the locomotor activity pattern (DOC 262 kb)

Supplemental Figure 2

Time course of ambulatory activity following administration of mGluR2/3 agonist LY379628 in Gβ5−/− and Gβ5+/+ mice. Activity of mice was tracked in 5-min bins over 180 min following administration of the drug. LY379628 does not cause measurable inhibition of the locomotor activity in Gβ5+/+ mice. Following initial habituation, mice maintained low but consistent level of motor unaffected by the drug administration. In contrast, Gβ5−/− mice failed to exhibit habituation behavior, but their activity was strongly inhibited by the drug (DOC 161 kb)

Supplemental Figure 3

Effects of amphetamine on activity of Gβ5−/− mice. Total distance travelled by wild-type Gβ5+/+ (n = 6) and Gβ5−/− (n = 6) mice was measured in the open field chamber for 3 h following i.p. amphetamine administration. ANOVA showed significant effect of amphetamine on activity of both Gβ5+/+ (F (2,15) = 92.085, p < 0.001) and Gβ5−/− mice (F (2,15) = 6.785, p < 0.01). Post hoc Tukey's test confirmed significant difference (*p < 0.05, **p < 0.01, ***p < 0.001 vs. saline control) where indicated. Error bars represent SEM values (DOC 135 kb)

Supplemental Table 1

Tissue content of dopamine (DA) and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) (DOC 148 kb)

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Xie, K., Ge, S., Collins, V.E. et al. Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems. Psychopharmacology 219, 823–834 (2012). https://doi.org/10.1007/s00213-011-2409-y

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