A Human Gene Polymorphism Reprograms Hormonal Signaling by Altering Kinase Recognition Sites: Identification of an SNP Generated Site of Phosphorylation

摘要

Human genetic variation alters individual susceptibility to disease, but the underlying mechanisms are still being elucidated. One class of human diseases, the channelopathies, has been shown to result from single nucleotide polymorphisms (SNPs) that disrupt the assembly and/or function of ion channel proteins. Using a combination of biochemistry, electrophysiology, and mass spectrometry, we show that a common polymorphism in the human ERG1 potassium channel gene, which is known to increase the risk of fatal cardiac arrhythmias, creates a novel recognition site on the channel for the Akt protein kinase that reverses the effects of hormonal signaling through the phosphatidylinositol 3 kinase on channel activity.