Dopamine receptor-interacting proteins: the Ca2+ connection in dopamine signaling

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Abstract

Abnormal activity of the dopamine system has been implicated in several psychiatric and neurological illnesses; however, lack of knowledge about the precise sites of dopamine dysfunction has compromised our ability to improve the efficacy and safety of dopamine-related drugs used in treatment modalities. Recent work suggests that dopamine transmission is regulated via the concerted efforts of a cohort of cytoskeletal, adaptor and signaling proteins called dopamine receptor-interacting proteins (DRIPs). The discovery that two DRIPs, calcyon and neuronal Ca2+ sensor 1 (NCS-1), are upregulated in schizophrenia highlights the possibility that altered protein interactions and defects in Ca2+ homeostasis might contribute to abnormalities in the brain dopamine system in neuropsychiatric diseases.

Section snippets

Dopamine receptor signaling complexes

Elucidating the complete array of DRIPs has now taken center stage in efforts to identify the players that are involved in the regulation of dopamine-mediated signaling. Many of the known DRIPs have been identified using the yeast two-hybrid (Y2H) system in which segments of a DA receptor are used to ‘fish out’ interacting proteins from brain cDNA libraries. A striking aspect of these screens is the finding that the D1 and D2 receptor subtypes appear to interact with two different sets of DRIPs

DRIPs: the Ca2+ connection

An intriguing idea to emerge from the functional characterization of DRIPs is the possibility that intracellular Ca2+ plays an important role in D1 and D2 receptor signaling. This notion is somewhat surprising in the face of more than a decade of research implicating cAMP as the principle effector in DA-mediated signaling [10]. Specifically, the D1-like receptor DRIP calcyon has been found to potentiate D1 and D5 receptor stimulation of the release of intracellular Ca2+ without compromising the

Calcyon and D1-like DA receptor Ca2+ signaling

Calcyon is a single-pass type III transmembrane protein oriented such that the N- terminus of the protein is intravesicular (or extracellular) and the C-terminus is cytoplasmic [30]. The sequence of calcyon is closely related to two integral membrane proteins P19 (also called NEEP21) and P21 33, 34, 35. NEEP21 was recently found to localize to early endosomes and to influence glutamate receptor recycling in neurons [35]. Initially isolated in a Y2H screen, subsequent pull-down and

NCS-1 and D2-like DA receptor function

NCS-1 was identified as a DRIP in a screen of a brain cDNA library using the carboxyl-terminal tail of the D2 receptor as ‘bait’ [29]. NCS-1 is the mammalian ortholog of Drosophila frequenin, an EF-hand Ca2+-binding protein [51] implicated in mediating several aspects of neurotransmission including ion channel regulation [52], neurotransmitter release [53] and intracellular protein trafficking [54]. NCS-1 is neuron specific [55] and exhibits an affinity for Ca2+ of 300 nM [56], which is within

Dopamine receptors, DRIPS, Ca2+ and psychiatric disorders

There are indications that abnormalities in calcyon and NCS-1 expression are associated with several CNS disorders. In particular, significant increases in the levels of both calcyon (by ∼100%) and NCS-1 (by ∼50%) have been found in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients 61, 62. The increases were unrelated to race, age, gender, alcohol or illicit drug abuse, postmortem period and brain pH. In addition, comparison of these two DRIPs in antipsychotic-treated and

The future

The identification of the DRIPs shown in Table 1 represents significant progress in our understanding of the protein interactions that regulate the intracellular activity of DA receptors in the CNS. Despite successes with Y2H approaches, the application of proteomics offers a much greater possibility of identifying the full array of proteins that are directly and indirectly associated with DA receptor signaling complexes in the brain. Recent advances in mass spectrometry permit hundreds of

Acknowledgements

This article is dedicated to the memory of Patricia S. Goldman-Rakic, who died on 31 July 2003. Center Grant P50 MH44866 (P.S.G-R., Principle Investigator); RO1 MH63271 (C. B.); National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award (R.L.).

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