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.
Huffaker
Stephen J
SJ
Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, Maryland, USA.
Chen
Jingshan
J
Nicodemus
Kristin K
KK
Sambataro
Fabio
F
Yang
Feng
F
Mattay
Venkata
V
Lipska
Barbara K
BK
Hyde
Thomas M
TM
Song
Jian
J
Rujescu
Dan
D
Giegling
Ina
I
Mayilyan
Karine
K
Proust
Morgan J
MJ
Soghoyan
Armen
A
Caforio
Grazia
G
Callicott
Joseph H
JH
Bertolino
Alessandro
A
Meyer-Lindenberg
Andreas
A
Chang
Jay
J
Ji
Yuanyuan
Y
Egan
Michael F
MF
Goldberg
Terry E
TE
Kleinman
Joel E
JE
Lu
Bai
B
Weinberger
Daniel R
DR
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