A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.
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.
Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, Maryland, USA.
Stephen J
SJ
Huffaker
Jingshan
J
Chen
Kristin K
KK
Nicodemus
Fabio
F
Sambataro
Feng
F
Yang
Venkata
V
Mattay
Barbara K
BK
Lipska
Thomas M
TM
Hyde
Jian
J
Song
Dan
D
Rujescu
Ina
I
Giegling
Karine
K
Mayilyan
Morgan J
MJ
Proust
Armen
A
Soghoyan
Grazia
G
Caforio
Joseph H
JH
Callicott
Alessandro
A
Bertolino
Andreas
A
Meyer-Lindenberg
Jay
J
Chang
Yuanyuan
Y
Ji
Michael F
MF
Egan
Terry E
TE
Goldberg
Joel E
JE
Kleinman
Bai
B
Lu
Daniel R
DR
Weinberger
D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011323:Primates; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D044465:White People / Q000235:genetics
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human