Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine‐treated animal model of schizophrenia and in postmortem schizophrenia brain

Seeman, P.; Ko, Françoise; Jack, Elaine; Greenstein, Rachel; Dean, Brian

doi:10.1002/syn.20368

Cited by 63 publications

(59 citation statements)

References 16 publications

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“…In the current study, we found a significant increase in the midbrain RGS2 and RGS4 mRNA levels 18 h following 5 days of AMPH self-administration. Reports on RGS2 mRNA levels following non-contingent AMPH treatment have not been consistent with no change (Burchett et al, 1998) and an increase (Seeman et al, 2007) owing to different lengths of AMPH treatment and withdrawal. These data suggest that AMPH modulates RGS2 mRNA levels in a brain region-dependent manner.…”

Section: Amph Self-administration Selectively Promoted Membrane Transmentioning

confidence: 93%

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Calipari

Sun

Eldeeb

et al. 2014

Neuropsychopharmacol

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Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drugseeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [ 35 S]GTPgS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gai2, whereas striatal D2/D3 receptors were coupled equally to Gai2 and Gao for signaling. Importantly, AMPH abolished the interaction between Gai2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gai2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction.

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Section: Amph Self-administration Selectively Promoted Membrane Transmentioning

confidence: 93%

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Calipari

Sun

Eldeeb

et al. 2014

Neuropsychopharmacol

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“…Dopaminergic pathways play a critical role in diseases such as Parkinson's disease (nigrostriatal system), schizophrenia, and addiction (mesolimbic and mesocortical system) (Li & Ma 2013). In schizophrenia, cortical D2Rs may be hypersensitive to dopamine (Seeman et al 2005(Seeman et al , 2007 or present in increased amounts in some regions. The prokineticin system is related to several physiological and pathological conditions (MaldonadoPerez et al 2007, Negri et al 2007, Zhou et al 2012.…”

Section: R68 Reviewmentioning

confidence: 99%

Oligomerization of GPCRs involved in endocrine regulation

Kleinau¹,

Müller²,

Biebermann³

2016

J Mol Endocrinol

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“…Similarly, GWAS studies have also indicated that another SNP in RGS6 (rs2332700) is significantly associated with schizophrenia (25). The possible significance of RGS6's role in schizophrenia is further supported by preliminary studies which also suggest that RGS7 and RGS9 may be differentially expressed in patients with schizophrenia (86,87) and may modulate brain responses to psychostimulants and antipsychotics (49,(88)(89)(90)(91)(92)(93). Finally, not only is there substantial evidence detailing the critical role of various R7 family members in proper vision (94-97) but a splice acceptor variant of RGS6 (c.1369-1G>C) has also been positively associated with the familial inheritance of congenital cataracts (26).…”

Section: Alzheimer's Disease Schizophrenia and Eye-related Disordersmentioning

confidence: 84%

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Ahlers

Chakravarti

Fisher

2016

AAPS J

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Abstract. Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gα i/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

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Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine‐treated animal model of schizophrenia and in postmortem schizophrenia brain

Cited by 63 publications

References 16 publications

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

Oligomerization of GPCRs involved in endocrine regulation

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

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