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      Interaction with Neuronal Calcium Sensor NCS-1 Mediates Desensitization of the D2 Dopamine Receptor

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          Abstract

          Dopaminergic transmission within limbic regions of the brain is highly dependent on the regulation of D2 receptor activity. Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. This effect of NCS-1 was accompanied by an increase in D2 receptor-mediated cAMP inhibition after dopamine stimulation. The ability of NCS-1 to modulate D2 receptor signaling was abolished after a single amino acid mutation in NCS-1 that has been shown to impair the calcium-binding properties of NCS-1. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. Colocalization of NCS-1 and D2 receptors was examined in both primate and rodent brain. In striatum, NCS-1 and D2 receptors were found to colocalize within sites of synaptic transmission and in close proximity to intracellular calcium stores. NCS-1–D2 receptor interaction may serve to couple dopamine and calcium signaling pathways, thereby providing a critical component in the regulation of dopaminergic signaling in normal and diseased brain.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          1 October 2002
          : 22
          : 19
          : 8476-8486
          Affiliations
          [ 1 ]Department of Pharmacology and
          [ 2 ]Neuroscience Graduate Program, Penn State College of Medicine, Hershey, Pennsylvania 17033, and
          [ 3 ]Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510
          Article
          PMC6757796 PMC6757796 6757796 6901
          10.1523/JNEUROSCI.22-19-08476.2002
          6757796
          12351722
          aaee0282-34b4-4752-9160-76160a1046c7
          Copyright © 2002 Society for Neuroscience
          History
          : 6 February 2002
          : 22 July 2002
          : 24 July 2002
          Categories
          ARTICLE
          Cellular/Molecular
          Custom metadata
          5.00

          calcium signaling,yeast two-hybrid,dopamine receptor,neuronal calcium sensor-1,GRK,GPCR desensitization,frequenin

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