IndraLab
Statements
sparser
"Later, Kurokawa et al reconstituted such effects in a recombinant expression system by coexpressing AKAP9 (Yotiao) and demonstrated that AKAP9 forms a macromolecular complex with KCNQ1, Type II regulatory subunit of PKA (RII), and protein phosphatase 1 (PP1) and brings PKA to the vicinity of the channel to phosphorylate a serine residue (S27) on KCNQ1 amino terminus xref ."
sparser
"Specifically, recent findings from Kass and Ackerman have identified AKAP9-S1570L which markedly diminishes the interaction of yotiao with KCNQ1, resulting in reduction in PKA-dependent phosphorylation of Kv7.1, and thus striking inhibition of I KS regulation by cAMP. xref Similar to models of LQT1 - associated mutations in KCNQ1 that block yotiao binding and I KS phospho-regulation, yotiao mutations are also predicted to prolong the action potential and increase arrhythmia susceptibility (now termed type 11 long QT syndrome). xref In support of this notion, the S1570L proband displayed a clinical LQTS phenotypes (now referred to as type 11 long QT syndrome; MIM#611820) similar to LQT1 mutations that block KCNQ1 association with yotiao (female, QT c 485 ms presenting with syncope and family history of LQTS). xref Together, these two related studies have revealed the critical importance of local regulation of ion channels by accessory ChIPs, as well as demonstrate the power of combining clinical genetics and molecular/cellular cardiology to drive disease discovery."
sparser
"Thus far, four non-ion channel LQTS-susceptibility genes have been discovered: (1) the ankyrin-B gene, which encodes a protein that functions as a cytoskeletal membrane adapter and is involved with the sodium pump, the sodium/calcium exchanger, and the inositol-1,4,5-triphosphate receptors, and can cause LQT4 when mutated ( xref ); (2) caveolin-3, which alters gating kinetics in the cardiac sodium channel, and if mutated may result in an increase in sustained late sodium current (Nav1.5; LQT9)( xref ; xref ); (3) AKAP9 (LQT11), mutation of which reduces the interaction between KCNQ1 and AKAP9 (Yotiao), reduces the cAMP-induced phosphorylation of the channel, eliminates the functional response of the IKs channel to cAMP, and prolongs the QT interval ( xref ); (4) SNTA1 (LQT12), which when mutated increases direct nitrosylation of SCN5A and results in augmentation of late sodium current ( xref )."
sparser
"In heart, sympathetic nervous system regulation of cardiac action potential duration, mediated by the βAR receptor, requires assembly of Yotiao with KCNQ1. xref The control of the sympathetic nervous system over the duration of cardiac action potential requires PKAmediated phosphorylation of the KCNQ1 subunit of the I Ks channel with the consequent increase in I Ks current, accelerated repolarization and increased heart rate."
reach
"51 The inherited S1570L mutation reduces the interaction between KCNQ1 and Yotiao, reduces the cAMP induced phosphorylation of the channel, eliminates the functional response of the IKs channel to cAMP, and prolongs the action potential in a computational model of the ventricular cardiac myocytes."
sparser
"A single mutation S1570L in Yotiao, localized to the C-terminal KCNQ1 binding domain, is found in 2% subjects with a clinically robust phenotype for LQT syndrome. xref The inherited S1570L mutation reduces the interaction between KCNQ1 and Yotiao, reduces the cAMP-induced phosphorylation of the channel, eliminates the functional response of the I Ks channel to cAMP, and prolongs the action potential in a computational model of the ventricular cardiac myocytes."