Abstract
Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT1A receptors or dopamine D4 receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT1A regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT1A effect. In contrast, the D4 regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT1A regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia.
Footnotes
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This work was supported by National Institutes of Health grants MH63128 and NS48911 and an Independent Investigator Award from NARSAD: The Mental Health Research Association (to Z.Y.).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.032490.
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ABBREVIATIONS: RGS, regulator of G protein signaling; GPCR, G protein-coupled receptor; PFC, prefrontal cortex; NMDAR, N-methyl-d-aspartate receptor; PCP, phencyclidine; DA, dopamine; NMDA, N-methyl-d-aspartate; EPSC, excitatory postsynaptic current; QX-314, (2,6-dimethylphenyl)carbamoylmethyl-triethyl-azanium; ANOVA, analysis of variance; GFP, green fluorescent protein; RT-PCR, reverse transcription-polymerase chain reaction; PBS, phosphate-buffered saline; bp, base pair(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; 8-OH-DPAT, 8-hydroxy-2-di-n-propylamino-tetralin; PD168077, N-methyl-4-(2-cyanophenyl)piperazynil-3-methylbenzamide maleate.
- Received November 8, 2006.
- Accepted January 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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