1Neurosci. Lett. 2011 Jan 487: 61-5
PMID20933057
TitleNo association between the KCNH1, KCNJ10 and KCNN3 genes and schizophrenia in the Han Chinese population.
Abstractschizophrenia is a common severe mental illness affecting 0.3-2.0% of the world's population. The potassium channels are thought to have a role in modulating electrical excitability in neurons, regulating calcium signaling in oligodendrocytes and regulating action potential duration in presynaptic terminals and GABA release. Previous studies have reported that some potassium channel genes might be candidate genes for susceptibility to schizophrenia. In the present study, we chose three potassium channel genes, KCNH1, KCNJ10, KCNN3 to investigate the role of potassium channels in schizophrenia by genotyping 23 SNPs (9 in KCNH1, 5 in KCNJ10 and 9 in KCNN3) in a Han Chinese sample consisting of 893 schizophrenia patients and 611 healthy controls. No significant difference in allelic or genotypic frequency was revealed between schizophrenia patients and healthy individuals. Nor was a significant difference in haplotypic distribution detected. MDR analysis revealed no gene-gene interaction within the three potassium channel genes. Our study suggests that the 23 SNPs within the three potassium genes we examined do not play a major role in schizophrenia in the Han Chinese population.
SCZ Keywordsschizophrenia
2Nature 2013 Sep 501: 444-8
PMID23975098
TitleThe structural mechanism of KCNH-channel regulation by the eag domain.
AbstractThe KCNH voltage-dependent potassium channels (ether--go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2? resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.
SCZ Keywordsschizophrenia