Semester

Summer

Date of Graduation

2019

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Bernard Schreurs

Committee Co-Chair

David Siderovski

Committee Member

David Siderovski

Committee Member

Vincent Setola

Committee Member

Steven Kinsey

Committee Member

Hanting Zhang

Committee Member

Thomas Kash

Abstract

Dopaminergic neurotransmission is critically involved in the etiology and treatment of many psychiatric and neurological disorders. One modulator of dopaminergic neurotransmission is the kappa opioid receptor (KOR) -- a G protein-coupled receptor (GPCR) that is densely expressed within dopaminergic neurons and circuits. GPCRs are tightly regulated by a variety of intracellular signaling molecules, including Regulator of G Protein Signaling (RGS) proteins. Canonically, RGS proteins act as GTPase accelerating proteins (GAPs) on GTP-bound Ga subunits following GPCR activation, thereby hastening the rate at which GPCR-mediated G protein signaling is terminated. However, some RGS proteins exhibit more complex mechanisms of action on cellular signaling. One such example is RGS12, which harbors the capacity to regulate both G protein-dependent and -independent signaling cascades. RGS12 is widely expressed across the developing and adult brain; we show that expression levels are notably high within dopamine- and KOR-enriched regions. We also observed that Rgs12 mRNA exhibits marked expression overlap with Oprk1 mRNA encoding KOR, which potently regulates dopaminergic neurotransmission following environmental stress and pharmacological challenge with psychostimulants. We revealed that genetic ablation of Rgs12 in mice upregulates dopamine transporter (DAT) function and attenuates behavioral responses to psychostimulants via KOR-dependent mechanisms. Moreover, we showed that RGS12 differentially regulates G protein-dependent versus G protein-independent signaling and behavior downstream of KOR activation. We also demonstrated that RGS12 displays region-specific effects in the striatum, and that RGS12 selectivity modulates KOR over other opioid receptors. Further studies are required to more completely elucidate the complex interaction between RGS12 and KOR, as well as to identify precisely the neuronal cell populations and brain regions mediating the effect of RGS12 on dopaminergic and KOR-dependent signal transduction and behavior.

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