title: Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor.
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.
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008253:Macaca mulatta; D046911:Macromolecular Substances; D008297:Male; D016297:Mutagenesis, Site-Directed; D051580:Neuronal Calcium-Sensor Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D002135:Calcium-Binding Proteins; C493593:DRD3 protein, human; C493595:Drd3 protein, rat; D046911:Macromolecular Substances; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011993:Recombinant Fusion Proteins; C101464:frequenin calcium sensor proteins; D000242:Cyclic AMP; D005982:Glutathione Transferase; D017868:Cyclic AMP-Dependent Protein Kinases; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D002118:Calcium; D004298:Dopamine