Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Abraham Kovoor

Abstract

Dopamine is the most widely distributed catecholamine neurotransmitter in the brain. D2-dopamine receptors (D2R) are one member of a receptor class, known as G-protein coupled receptors, which transduce cellular signals upon an interaction with dopamine. Historically, it was believed that in schizophrenic patients, an excess of dopaminergic signaling at D2R was the cause of psychotic symptoms. Thus, antipsychotics reversed psychosis by blocking excessive dopaminergic signaling from D2R. Sixty years after the introduction of antipsychotic drugs, the connection between the anti-dopaminergic activity of these drugs at D2R and the suppression of psychotic symptoms remains unknown. Understanding the ways that different molecules mediate changes in the ability of D2R to signal and internalize, and thereby affect its cellular compartmentalization is critical to our development of potent antipsychotic agents with fewer side effects. Upon dopamine binding to the receptor, D2R is thought to generate an intracellular signal or signals by activating a heterotrimeric α-β-γ Gprotein that is a component of the receptor complex. In contrast to other G protein beta subunits, Gβ5 is a unique beta subunit that has not been shown to interact with other heterotrimeric G proteins in vivo. Previously, it was assumed that regulators of G-protein signaling (RGSs, specifically the R7 RGS family of proteins) and Gβ5 are required for the physiological activity of Gβ5. Here we show that no R7 RGS proteins are required for Gβ5 to interact with both compartmentalized and non-compartmentalized forms of D2R. Additionally, we have identified one way that Gβ5 may modulate D2R signaling, by specifically blocking the internalization of the receptor in response to dopamine without disrupting the G protein signaling. All currently available antipsychotics have been demonstrated to bind to and inhibit D2R receptors. Despite their strong anti-dopaminergic action, the efficacy of antipsychotic agents is limited by the serious side effects that these drugs produce, such as tardive dyskinesia and metabolic syndromes. Clozapine, a uniquely efficacious antipsychotic drug, produces reductions in schizophrenic symptoms without manifesting the common adverse effects of other antipsychotics. Therefore we have reexamined the effects of clozapine on D2R biochemistry, specifically how cellular compartmentalization of D2R may be affected by antipsychotic treatment. We found that all antipsychotics tested significantly increased the surface localization, as well as enhancing the solubility, of D2R; with the sole exception of clozapine. This new paradigm may explain clozapine’s unique therapeutic efficacy. This discovery could lead to the developments of new therapeutic agents that produce less significant side effects, and more potent reduction of schizophrenic symptoms than the currently available antipsychotic agents

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