A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia

被引：204

作者：

Huffaker, Stephen J. ^{[1
,2
]}

Chen, Jingshan ^{[1
,2
]}

Nicodemus, Kristin K. ^{[1
,2
]}

Sambataro, Fabio ^{[1
,2
]}

Yang, Feng ^{[3
]}

Mattay, Venkata ^{[1
,2
]}

Lipska, Barbara K. ^{[1
,2
]}

Hyde, Thomas M. ^{[1
,2
]}

Song, Jian ^{[1
,2
]}

Rujescu, Dan ^{[4
]}

Giegling, Ina ^{[4
]}

Mayilyan, Karine ^{[5
]}

Proust, Morgan J. ^{[1
]}

Soghoyan, Armen ^{[5
]}

Caforio, Grazia ^{[6
]}

Callicott, Joseph H. ^{[1
]}

Bertolino, Alessandro ^{[6
]}

Meyer-Lindenberg, Andreas ^{[1
,2
]}

Chang, Jay ^{[2
,3
]}

Ji, Yuanyuan ^{[3
]}

Egan, Michael F. ^{[1
]}

Goldberg, Terry E. ^{[1
,2
]}

Kleinman, Joel E. ^{[1
,2
]}

Lu, Bai ^{[2
,3
]}

Weinberger, Daniel R. ^{[1
,2
]}

机构：

[1] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA

[2] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA

[3] NICHD, Sect Neural Dev & Plast, Bethesda, MD USA

[4] Univ Munich, Dept Psychiat, D-8000 Munich, Germany

[5] Yerevan State Med Univ, Dept Psychiat & Med Psychol, Hlth Minist Armenian, Yerevan, Armenia

[6] Univ Bari, Dept Neurol & Psychiat Sci, Sect Mental Disorders, Psychiat Neurosci Grp, Bari, Italy

来源：

NATURE MEDICINE | 2009年 / 15卷 / 05期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; GENOTYPE-PHENOTYPE ASSOCIATIONS; DORSOLATERAL PREFRONTAL CORTEX; GENETIC ASSOCIATIONS; WORKING-MEMORY; RELATIVE RISK; K+ CHANNELS; HERG; SIBLINGS; OSCILLATIONS;

D O I：

10.1038/nm.1962

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K+ channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.

引用

页码：509 / 518

页数：10

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