Migration of PIP2 lipids on voltage-gated potassium channel surface influences channel deactivation.

Published studies of lipid-protein interactions have mainly focused on lipid binding to an individual site of the protein. Here, we show that a lipid can migrate between different binding sites in a protein and this migration modulates protein function. Voltage-gated potassium (Kv) channels have several potential binding sites for phosphatidylinositol-4,5-bisphosphate (PIP2). Our molecular dynamics (MD) simulations on the KCNQ2 channel reveal that PIP2 preferentially binds to the S4-S5 linker when the channel is in the open state while maintains a certain probability of migrating to the S2-S3 linker. Guided by the MD results, electrophysiological experiments using KCNQ2, KCNQ1, and hERG channels show that the migration of PIP2 toward the S2-S3 linker controls the deactivation rate of the channel. The data suggest that PIP2 can migrate between different binding sites in Kv channels with significant impacts on channel deactivation, casting new insights into the dynamics and physiological functions of lipid-protein interactions.

Influence of genetic polymorphisms involved in the hypothalamic-pituitary-adrenal axis and their interactions with environmental factors on antidepressant response.

AIMS: To investigate the role of genetic polymorphisms in candidate genes associated with the HPA axis and their interactions with environmental stressors in antidepressant response. METHODS: The remission of depressive symptoms after 8 weeks of antidepressant treatment was tested against 21 single nucleotide polymorphisms (SNPs) in five candidate genes associated with the HPA axis in a Chinese Han sample suffering from unipolar depression (n = 273). Any history of childhood trauma and recent negative life events were measured using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) (n = 206) and the Life Event Scale (48 item, LES) (n = 207), respectively. Reporter gene assays were used to evaluate the possible effects of the most significant SNP on gene expression. RESULTS: A functional polymorphism at 3'UTR of the corticotropin-releasing hormone receptor 1 (CRHR1) gene (rs28364032) and three haplotypes containing it showed significant relationships with antidepressant remission. Further laboratory-based genomic studies showed that the G-to-A change of rs28364032 resulted in a 10-12% decrease in the intensity of luciferase activity. However, we failed to find association of environments and their interaction with HPA system-related genes with antidepressant remission. CONCLUSIONS: Our results support a definite role for CRHR1 in the pharmacogenetics of antidepressant drugs. This may contribute to interpatient differences in their responses to antidepressant drugs.