| 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
Voltage-dependent ion channels underlie the propagation of action potentials and other forms of electrical activity in cells. In these proteins, voltage sensor domains (VSDs) regulate opening and closing of the pore through the displacement of their positive-charged S4 helix in response to the membrane voltage. The movement of S4 at hyperpolarizing membrane voltages in some channels is thought to directly clamp the pore shut through the S4-S5 linker helix. The KCNQ1 channel (also known as K(v)7.1), which is important for heart rhythm, is regulated not only by membrane voltage but also by the signaling lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)). KCNQ1 requires PIP(2) to open and to couple the movement of S4 in the VSD to the pore. To understand the mechanism of this voltage regulation, we use cryogenic electron microscopy to visualize the movement of S4 in the human KCNQ1 channel in lipid membrane vesicles with a voltage difference across the membrane, i.e., an applied electric field in the membrane. Hyperpolarizing voltages displace S4 in such a manner as to sterically occlude the PIP(2)-binding site. Thus, in KCNQ1, the voltage sensor acts primarily as a regulator of PIP(2) binding. The voltage sensors' influence on the channel's gate is indirect through the reaction sequence: voltage sensor movement --> alter PIP(2) ligand affinity --> alter pore opening.
The membrane electric field regulates the PIP(2)-binding site to gate the KCNQ1 channel.,Mandala VS, MacKinnon R Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2301985120. doi: , 10.1073/pnas.2301985120. Epub 2023 May 16. PMID:37192161[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Mandala VS, MacKinnon R. The membrane electric field regulates the PIP(2)-binding site to gate the KCNQ1 channel. Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2301985120. PMID:37192161 doi:10.1073/pnas.2301985120
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