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

2009; Nature Portfolio; Volume: 15; Issue: 5 Linguagem: Inglês

10.1038/nm.1962

1546-170X

Stephen J. Huffaker, Jingshan Chen, Kristin K. Nicodemus, Fabio Sambataro, Feng Yang, Venkata S. Mattay, Barbara K. Lipska, Thomas M. Hyde, Jian Song, Dan Rujescu, Ina Giegling, Karine R. Mayilyan, Morgan J Proust, Armen Soghoyan, Grazia Caforio, Joseph H. Callicott, Alessandro Bertolino, Andreas Meyer‐Lindenberg, Jay Chang, Yuanyuan Ji, Michael Egan, Terry E. Goldberg, Joel E. Kleinman, Bai Lu, Daniel R. Weinberger,

Receptor Mechanisms and Signaling

Polymorphisms in a primate-specific isoform of K+ channel KCNH2 are associated with schizophrenia. This isoform induces a rapidly deactivating K+ current and high-frequency neuronal firing pattern. The disease-associated alleles predict lower intelligence quotient scores, lower speed of cognitive processing and altered memory. This channel isoform represents a potential new drug target for psychotherapy pages 488–490 . 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.