Review
A proteomic approach to receptor signaling: Molecular mechanisms and therapeutic implications derived from discovery of the dopamine D2 receptor signalplex

https://doi.org/10.1016/j.ejphar.2007.06.059Get rights and content

Abstract

Recent research in cell signaling has shown that the assembly of G protein coupled receptors into signaling complexes or signalplexes represents the primary mechanism by which receptor-mediated signaling is established and maintained. In this review, we summarize the current state of knowledge regarding protein interactions that comprise the dopamine D2 receptor signalplex within the brain. Studies based on conventional and advanced two-hybrid methodologies, as well as bioinformatic and computational analysis of sequence information from completed genomes have demonstrated interactions between dopamine D2 receptors and a cohort of dopamine receptor interacting proteins (DRIPs). DRIP interactions appear to regulate key aspects of receptor function including the signaling and membrane trafficking of dopamine D2 receptors. Disruptions or modifications of the signalplex, using membrane permeant competing peptide or dominant negative approaches, may represent promising new strategies for the selective targeting of the dopamine D2 receptor in cells and in native tissue. DRIP interactions provide a novel platform for understanding the mechanisms of dopamine receptor signaling, and for the potential development of novel treatments for brain disease.

Introduction

Dopamine receptors are members of a large family of structurally related G protein coupled receptors that share a high degree of homology to rhodopsin (Stenkamp et al., 2005). In various species, dopamine mediates a number of important neural functions including the regulation of motor, memory, attention, reward, and neuroendocrine processes (Bertorello et al., 1990, Goldman-Rakic, 1998, Schultz, 2002). Dopamine receptors thus play an essential role in physiological mechanisms of the central nervous system, and are common targets of therapeutic drugs aimed at alleviating human pathologic conditions such as schizophrenia and Parkinson's disease (Strange, 2001).

Cloning of the dopamine receptor genes has led to the identification of five receptor subtypes, which are commonly classified into two subfamilies (D1-like and D2-like) based on pharmacologic profiles and sequence similarities (Missale et al., 1998, Sidhu and Niznik, 2000). D1-like receptors (D1 and D5) are structurally characterized by a short third cytoplasmic loop, a long C-terminal tail, and the ability to activate “stimulatory” GTP binding proteins (G proteins) within cells. In contrast, D2-like receptors (D2, D3, and D4) are characterized by a large third cytoplasmic loop, a short C-terminal tail, and the ability to activate “inhibitory” G proteins (Obadiah et al., 1999).

Human genes encoding the five dopamine receptors are located on different chromosomes, with genes for D1-like receptors lacking introns, and genes for D2-like receptors containing introns (Missale et al., 1998). In mammals, mRNA splicing generates two isoforms of the dopamine D2 receptor: D2 long (D2L) and D2 short (D2S) which differ by the inclusion of a 29 amino acid segment in the third cytoplasmic loop of D2L (Neve et al., 2004). While D2L and D2S are believed to interact with similar pertussis toxin-sensitive G proteins, studies reveal that these receptor isoforms are targeted to post and presynaptic neuronal compartments, respectively, and contribute to different aspects of dopamine transmission (Lindgren et al., 2003).

Dopamine exerts its fast (short-term) effects on cellular excitability by regulating a number of ligand- and voltage-gated ion channels, transporters, and the sodium–potassium pump (Na+ K+ ATPase) (Bertorello et al., 1990, Nicola et al., 2000). In addition, the activation of dopamine D2 receptors is linked to signaling via various molecules such as: Protein Kinase A (PKA); Protein Kinase C (PKC); neuronal Nitric Oxide Synthase (nNOS); Calmodulin Kinase II (CaMK II); calcineurin; and Protein Phosphatase 1 and 2 (PP-1 and PP-2) (Neve et al., 2004). In recent years, it has become evident that the diverse cellular properties of dopamine receptors are mediated by their interaction with a class of molecules collectively termed dopamine receptor interacting proteins (DRIPs). DRIPs not only regulate receptor signaling, but contribute to receptor trafficking and stability, and to the formation of the dopamine receptor signalplex in cells. Many of the functional properties that distinguish receptor subtypes appear to be determined by their differential protein interactions, a theory supported by findings that the dopamine D1 and D2 receptors interact with a different set of DRIPs (Bergson et al., 2003). The discovery of DRIPs demarcates a new path for understanding the mechanism of dopamine receptor function, and in advancing drug design for brain disease.

Section snippets

Signalplexes in G protein coupled receptor signaling

G protein coupled receptors form the largest receptor family in mammalian genomes, and are molecular targets for drugs used to treat neurologic disease (Bockaert et al., 2004b, Tabata and Kano, 2004). Amongst the signature components of G protein coupled receptors are seven hydrophobic transmembrane helices connected via four extracellular and three intracellular (cytoplasmic) loops, and a cytoplasmic C-terminal tail (El Far and Betz, 2002). The cytoplasmic segments of the receptor have been

Novel protein interactions of the dopamine D2 receptor

Here we summarize the current state of knowledge regarding protein interactions of the dopamine D2 receptor signalplex (a comprehensive list of dopamine D2 receptor interactions is presented in Table 1). It is important to note that the analysis of DRIP interactions suggests that signalplex components are composed of both direct and indirect protein interactions with the dopamine D2 receptor (Fig. 1).

The dopamine receptor signalplex in brain disease

Abnormalities in dopamine transmission are predicted to underlie a number of neurological and psychiatric conditions ranging from Parkinson's disease to drug abuse, Tourette's syndrome, and depression (Girault and Greengard, 2004). Foremost is the “dopamine hypothesis” of schizophrenia, formulated over 30 years ago as based on Carlsson's observation that treatment of rats with antipsychotic drugs caused changes in the levels of dopamine metabolites, and that these changes reflected an

Conclusion

Characterization of the dopamine D2 receptor signalplex, a primary molecular component of the cortical and limbic pathway and an important target in antipsychotic and antiparkinsonian drug development, represents a significant endeavor. The identification of signalplex components promises to provide information on the cellular processes associated with dopamine receptor activation, and the mechanisms of G protein coupled receptor signaling in cells. Elucidating the complete array of dopamine

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