Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Proteins Interacting With the Third Cytoplasmic Loop of Dopamine D2 and D3 Receptors

Abstract

Abstract. Among the various dopamine receptors, D 2 -like receptors (D2R, D3R, and D4R) are characterized by a large third cytoplasmic loop, a short carboxyl-terminal tail, and the ability to activate inhibitory G proteins. The diverse activities of D 2 -like receptors are partly mediated by proteins that interact with the third cytoplasmic loop, which regulate receptor signaling, receptor trafficking, and stability. Furthermore, in the case of D2R and D3R genes, mRNA splicing generates isoforms in the region of the third cytoplasmic loop. The gene encoding D2R gives rise to two isoforms, termed the dopamine D 2 receptor long isoform (D2LR) and the dopamine D 2 receptor short isoform (D2SR), which lacks 29 amino acids of the D2LR within the third cytoplasmic loop. The D3R gene also produces at least seven distinct alternative splicing variants including D3nf, in which 98 base pairs in the carboxyl-terminal region of the third intracellular loop are deleted. In this review, we focus on proteins interacting with the dopamine D 2 /D 3 receptors in the third cytoplasmic loop. We also define a novel binding protein, heart-type fatty acid-binding protein (H-FABP), which specifically interacts with the 29 D2LR amino acids deleted in D2SR and document its function in D2LR signaling.

D2‐Dopamine receptors target regulator of G protein signaling 9‐2 to detergent‐resistant membrane fractions

“…The finding that the majority of brain D 2 R is expressed DRM fractions has exposed a major limitation of common approaches for identifying components of the D 2 R signaling complex in the brain. Due to the physiological and clinical importance of D 2 R, a large amount of such effort has been invested in identifying the different protein interactions that comprise the D 2 R ‘signalplex’ (Kabbani and Levenson 2007; Shioda et al. 2010).…”

Uncoupling DISC1 × D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors

“…Studies of D2R interacting proteins, using yeast two-hybrid, co-immunoprecipitation, glutathione S-transferase (GST) pull-down and in vitro binding assays, have identified about 20 proteins with many of them relevant to schizophrenia (Wang et al, 2008 ; Shioda et al, 2010 ; Kabbani et al, 2012 ). These proteins selectively regulate specific signaling pathways and function of D2R via protein-protein interactions, without affecting other signaling pathways.…”

Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma

“…Previous studies reported that some FABPs, such as H-FABP or B-FABP, could interact with membrane-associated receptors, including integrin or dopamine D2 receptor [ 9 – 11 ], and that L-FABP may associate with cell membranes or membrane proteins [ 5 , 12 ]. A recent study also revealed that L-FABP was significantly associated with hepatocyte plasma membrane cholesterol-rich microdomains [ 13 ].…”