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Role of the Dopamine D3 Receptor Signaling Complex in the receptor Tolerance and Slow Response Termination properties

Dopamine is a predominant neurotransmitter and improper regulation of dopaminergic transmission results in disorders such as Parkinson's disease, schizophrenia and addiction. Dopamine receptors are G‐protein coupled receptors (GPCRs) and are classified as D1‐D5. Although the D3 receptor (D3R) shares high homology with D2, it possesses distinct signaling properties when repeatedly stimulated with agonist. The D3R exhibits two unique signaling properties, tolerance and slow response termination (SRT) to Dopamine and classical D2‐like receptor agonists. Tolerance is defined as a reduction in signaling response upon a second exposure to agonist and SRT is seen as a slow termination of the response upon agonist removal. GPCRs interact with a variety of proteins including but not limited to their cognate G‐protein, regulatory and modulatory proteins such as Regulator of G protein Signaling proteins, Kinases and Phosphatases. The molecular mechanisms underlying the D3R tolerance and SRT are unknown. We hypothesized that the D3R and D2R interacts with a different set of proteins and differences in this signaling complex contributes to the phenomena of Tolerance and SRT. Our results suggest that the D2R and D3R couple to different Gαi/o proteins, suggesting a role for the G proteins in the D3R tolerance and SRT properties. Sucrose density gradient experiments indicated that the molecular mass of the D3R is different in the tolerant and non‐tolerant states while Mass Spectrometry analysis identified specific proteins interacting with the D3R in its tolerant state.