| Structural highlights
Disease
KCNQ1_HUMAN Defects in KCNQ1 are the cause of long QT syndrome type 1 (LQT1) [MIM:192500; also known as Romano-Ward syndrome (RWS). Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT1 inheritance is an autosomal dominant.[1] [2] [3] [4] [5] [6] [7] [:][8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] Defects in KCNQ1 are the cause of Jervell and Lange-Nielsen syndrome type 1 (JLNS1) [MIM:220400. JLNS1 is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death.[28] [29] [30] Defects in KCNQ1 are the cause of familial atrial fibrillation type 3 (ATFB3) [MIM:607554. Atrial fibrillation is a common disorder of cardiac rhythm that is hereditary in a small subgroup of patients. It is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.[31] Defects in KCNQ1 are the cause of short QT syndrome type 2 (SQT2) [MIM:609621. Short QT syndromes are heart disorders characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. They cause syncope and sudden death.[32]
Function
KCNQ1_HUMAN Probably important in cardiac repolarization. Associates with KCNE1 (MinK) to form the I(Ks) cardiac potassium current. Elicits a rapidly activating, potassium-selective outward current. Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current in CHO cells in which cloned KCNQ1/KCNE1 channels were coexpressed with M1 muscarinic receptors. May associate also with KCNE3 (MiRP2) to form the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions, which is reduced in cystic fibrosis and pathologically stimulated in cholera and other forms of secretory diarrhea.
Publication Abstract from PubMed
The cardiac KCNQ1 potassium channel carries the important I(Ks) current and controls the heart rhythm. Hundreds of mutations in KCNQ1 can cause life-threatening cardiac arrhythmia. Although KCNQ1 structures have been recently resolved, the structural basis for the dynamic electro-mechanical coupling, also known as the voltage sensor domain-pore domain (VSD-PD) coupling, remains largely unknown. In this study, utilizing two VSD-PD coupling enhancers, namely, the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)) and a small-molecule ML277, we determined 2.5-3.5 A resolution cryo-electron microscopy structures of full-length human KCNQ1-calmodulin (CaM) complex in the apo closed, ML277-bound open, and ML277-PIP(2)-bound open states. ML277 binds at the "elbow" pocket above the S4-S5 linker and directly induces an upward movement of the S4-S5 linker and the opening of the activation gate without affecting the C-terminal domain (CTD) of KCNQ1. PIP(2) binds at the cleft between the VSD and the PD and brings a large structural rearrangement of the CTD together with the CaM to activate the PD. These findings not only elucidate the structural basis for the dynamic VSD-PD coupling process during KCNQ1 gating but also pave the way to develop new therapeutics for anti-arrhythmia.
Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.,Ma D, Zhong L, Yan Z, Yao J, Zhang Y, Ye F, Huang Y, Lai D, Yang W, Hou P, Guo J Proc Natl Acad Sci U S A. 2022 Nov 8;119(45):e2207067119. doi: , 10.1073/pnas.2207067119. Epub 2022 Nov 3. PMID:36763058[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Ma D, Zhong L, Yan Z, Yao J, Zhang Y, Ye F, Huang Y, Lai D, Yang W, Hou P, Guo J. Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers. Proc Natl Acad Sci U S A. 2022 Nov 8;119(45):e2207067119. PMID:36763058 doi:10.1073/pnas.2207067119
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