Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract??? KCNQ1 (Kv7.1 or KvLQT1) encodes the alpha-subunit of a voltage-gated potassium channel found in tissues including heart, brain, epithelia and smooth muscle. Tissue-specific characteristics of KCNQ1 current are diverse, due to modification by ancillary subunits. In heart, KCNQ1 associates with KCNE1 (MinK), producing a slowly activating voltage-dependent channel. In epithelia, KCNQ1 co-assembles with KCNE3 (Mirp2) producing a constitutively open channel. Chromanol 293B is a selective KCNQ1 blocker. We studied drug binding and frequency dependence of 293B on KCNQ1 and ancillary subunits expressed in Xenopus oocytes. Ancillary subunits altered 293B potency up to 100-fold (IC(50) for KCNQ1 = 65.4 +/- 1.7 microm; KCNQ1/KCNE1 = 15.1 +/- 3.3 microm; KCNQ1/KCNE3 = 0.54 +/- 0.18 microm). Block of KCNQ1 and KCNQ1/KCNE3 was time independent, but 293B altered KCNQ1/KCNE1 activation. We therefore studied frequency-dependent block of KCNQ1/KCNE1. Repetitive rapid stimulation increased KCNQ1/KCNE1 current biphasically, and 293B abolished the slow component. KCNQ1/KCNE3[V72T] activates slowly with a KCNQ1/KCNE1-like phenotype, but retains the high affinity binding of KCNQ1/KCNE3, demonstrating that subunit-mediated changes in gating can be dissociated from subunit-mediated changes in affinity. This study demonstrates the KCNQ1 pharmacology is significantly altered by ancillary subunits. The response of KCNQ1 to specific blockers will therefore be critically dependent on the electrical stimulation pattern of the target organ. Furthermore, the dissociation between gating and overall affinity suggests that mutations in ancillary subunits can potentially strongly alter drug sensitivity without obvious functional changes in gating behaviour, giving rise to unexpected side-effects such as a predisposition to acquired long QT syndrome.
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995, Pubmed
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995,
Pubmed
Bett,
KChIP2b modulates the affinity and use-dependent block of Kv4.3 by nifedipine.
2006,
Pubmed
,
Xenbase
Bett,
Inactivation and recovery in Kv1.4 K+ channels: lipophilic interactions at the intracellular mouth of the pore.
2004,
Pubmed
,
Xenbase
Bleich,
KVLQT channels are inhibited by the K+ channel blocker 293B.
1997,
Pubmed
,
Xenbase
Brahmajothi,
In situ hybridization reveals extensive diversity of K+ channel mRNA in isolated ferret cardiac myocytes.
1996,
Pubmed
Chouabe,
Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias.
1997,
Pubmed
Demolombe,
Differential expression of KvLQT1 and its regulator IsK in mouse epithelia.
2001,
Pubmed
Gould,
Imprinting of mouse Kvlqt1 is developmentally regulated.
1998,
Pubmed
Jentsch,
Neuronal KCNQ potassium channels: physiology and role in disease.
2000,
Pubmed
Lan,
Electrophysiological and molecular identification of hepatocellular volume-activated K+ channels.
2005,
Pubmed
Mason,
Molecular basis of voltage-dependent potassium currents in porcine granulosa cells.
2002,
Pubmed
Melman,
Structural determinants of KvLQT1 control by the KCNE family of proteins.
2001,
Pubmed
Melman,
A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating.
2002,
Pubmed
Melman,
KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity.
2004,
Pubmed
Neyroud,
A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.
1997,
Pubmed
Panaghie,
Interaction of KCNE subunits with the KCNQ1 K+ channel pore.
2006,
Pubmed
,
Xenbase
Pusch,
Two open states and rate-limiting gating steps revealed by intracellular Na+ block of human KCNQ1 and KCNQ1/KCNE1 K+ channels.
2001,
Pubmed
Sanguinetti,
Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.
1996,
Pubmed
,
Xenbase
Schroeder,
A constitutively open potassium channel formed by KCNQ1 and KCNE3.
2000,
Pubmed
,
Xenbase
Seebohm,
Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels.
2005,
Pubmed
,
Xenbase
Seebohm,
Differential roles of S6 domain hinges in the gating of KCNQ potassium channels.
2006,
Pubmed
,
Xenbase
Seebohm,
Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome.
2001,
Pubmed
,
Xenbase
Seebohm,
A kinetic study on the stereospecific inhibition of KCNQ1 and I(Ks) by the chromanol 293B.
2001,
Pubmed
,
Xenbase
Seebohm,
Molecular determinants of KCNQ1 channel block by a benzodiazepine.
2003,
Pubmed
,
Xenbase
Seebohm,
Tight coupling of rubidium conductance and inactivation in human KCNQ1 potassium channels.
2003,
Pubmed
,
Xenbase
Tristani-Firouzi,
Voltage-dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits.
1998,
Pubmed
,
Xenbase
Tsevi,
KCNQ1/KCNE1 channels during germ-cell differentiation in the rat: expression associated with testis pathologies.
2005,
Pubmed
Vetter,
Inner ear defects induced by null mutation of the isk gene.
1996,
Pubmed
Wang,
Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect.
2003,
Pubmed
,
Xenbase
Wang,
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
1996,
Pubmed
Wang,
Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation.
1997,
Pubmed
,
Xenbase
Wulfsen,
Expression of mRNA for voltage-dependent and inward-rectifying K channels in GH3/B6 cells and rat pituitary.
2000,
Pubmed
Yang,
KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias.
1997,
Pubmed
,
Xenbase
Yeola,
Molecular analysis of a binding site for quinidine in a human cardiac delayed rectifier K+ channel. Role of S6 in antiarrhythmic drug binding.
1996,
Pubmed
Zhou,
Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.
2001,
Pubmed
,
Xenbase
