2006 Fiscal Year Final Research Report Summary
Functional analysis of mutation and partial duplication of α7 nicotinic receptor subunit gene : implication in schizophrenia
| Project/Area Number |
16590435
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | University of Toyama (2005-2006)
Toyama Medical and Pharmaceutical University (2004) |
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Principal Investigator |
TSUNEKI Hiroshi University of Toyama, Graduate School of Medicine and Pharmaceutical Science for Research, Associate Professor, 医学薬学研究部, 助教授 (20332661)
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| Co-Investigator(Kenkyū-buntansha) |
KURACHI Masayoshi University of Toyama, Graduate School of Medicine and Pharmaceutical Science for Research, Professor, 医学薬学研究部, 教授 (80019603)
TSUNODA Masahiko Toyama University Hospital, Assistant Professor, 附属病院, 助手 (30322762)
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| Project Period (FY) |
2004 – 2006
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| Keywords | nicotinic receptors / acetylcholine / schizophrenia / single nucleotide polymorphism / gene mutation / desensitization / protein kinase C / phosphorylation |
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| Research Abstract |
1. The α7 nicotinic receptor subunit (CHRNA7) gene has been considered as a susceptible gene for schizophrenia. In this study, we found a novel mutation in CHRNA7 gene in a Japanese schizophrenic patient. Since the mutation results in amino acid substitution (G423S) in the receptor cytoplasmic loop, we investigated functional differences between wild-type (WT) and the α7-G423S mutant receptor expressed in Xenopus oocytes. In the presence of a protein kinase C (PKC) activator, stimulation with α7 agonist induces phosphorylation and inhibition of the α7-G423S mutant receptor, but not WT receptor. These results demonstrate that the G423S mutation promotes the receptor desensitization by a protein kinase C-dependent mechanism.
2. The CHRNA7 gene is partially duplicated and forms a hybrid (CHRFAM7A) with a novel gene FAM7A. In this study, we found that the cDNA of CHRFAM7A gene was translated into protein (dup-α7) in Xenopus oocytes and human SH-SY5Y cells, and that the protein was coimmunoprecipitated with α7 receptor subunit. Moreover, electrophysiological and biochemical studies demonstrated that the expression of dup-α7 protein caused the reduction of α7 receptor activity. These findings suggest the existence of a novel mechanism for regulating α7 receptor activity via dup-α7 protein.
3. We examined effects of several alkaloids from amphibians and ascidians on neuronal nicotinic receptors, and found that the alkaloid (+)-205B is a patent and selective blocker of α7 nicotinic receptor.
4. We found that chronic nicotine stimulation caused enhanced expression of gonadotropin releasing hormone in hypothalamic GT1-7 cells via t nicotinic receptor, and upregulation of α7 nicotinic receptor in vascular smooth muscle cells.
These results suggest that the G423S mutation in CHRNA7 and the dup-α7 protein excess perturb the function of α7 nicotinic receptor and serve as predisposing factors for central cholinergic disorders, such as schizophrenia.
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