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.
Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect.
Wang S
,
Morales MJ
,
Qu YJ
,
Bett GC
,
Strauss HC
,
Rasmusson RL
.
???displayArticle.abstract???
We studied quinidine block of Kv1.4DeltaN, a K(+) channel lacking N-type inactivation, expressed in Xenopus ooctyes. Initially, quinidine intracellularly blocked the open channel so rapidly it overlapped with activation. This rapid open channel block was reduced (non-additively) by interventions that slow C-type inactivation: [K(+)](o) elevation and an extracellular lysine to tyrosine mutation (K532Y). These manipulations reduced the affinity of rapid open channel block ~10-fold, but left the effective electrical distance unchanged at ~0.15. Following rapid open channel block, there were time-dependent quinidine effects: the rate of inactivation during a single depolarisation was increased, and repetitive pulsing showed use dependence. The rate of recovery from the time-dependent aspect of quinidine block was similar to recovery from normal C-type inactivation. Manipulations that prevented the channel from entering the C-type inactivated state (i.e. high [K(+)](o) or the K532Y mutation) prevented the development of the time-dependent quinidine-induced inactivation. The concentration dependence of the rapid block and the time-dependent quinidine-induced inactivation were similar, but the time-dependent component was strongly voltage sensitive, with an effective electrical distance of 2. Clearly, this cannot reflect the permeation of quinidine through the electric field, but must be the result of some other voltage-sensitive change in the channel. We propose that quinidine promotes the entry of the channel into a C-type inactivated state in a time- and voltage-dependent manner. We developed a mathematical model based on these results to test the hypothesis that, following rapid open channel block, quinidine promotes development of the C-type inactivated state through a voltage-dependent conformational change.
Balser,
Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine and amiodarone.
1991, Pubmed
Balser,
Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine and amiodarone.
1991,
Pubmed
Balser,
External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels.
1996,
Pubmed
,
Xenbase
Baukrowitz,
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
1995,
Pubmed
Baukrowitz,
Use-dependent blockers and exit rate of the last ion from the multi-ion pore of a K+ channel.
1996,
Pubmed
Baukrowitz,
Two functionally distinct subsites for the binding of internal blockers to the pore of voltage-activated K+ channels.
1996,
Pubmed
Bezanilla,
Molecular basis of gating charge immobilization in Shaker potassium channels.
1991,
Pubmed
,
Xenbase
Brahmajothi,
Distinct transient outward potassium current (Ito) phenotypes and distribution of fast-inactivating potassium channel alpha subunits in ferret left ventricular myocytes.
1999,
Pubmed
Chen,
Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels.
2002,
Pubmed
,
Xenbase
Chen,
On the mechanism by which 4-Aminopyridine occludes quinidine block of the cardiac K+ channel, hKv1.5.
1998,
Pubmed
Choi,
Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels.
1991,
Pubmed
Clark,
Quinidine-induced open channel block of K+ current in rat ventricle.
1995,
Pubmed
Comer,
Cloning and characterization of an Ito-like potassium channel from ferret ventricle.
1994,
Pubmed
,
Xenbase
Demo,
The inactivation gate of the Shaker K+ channel behaves like an open-channel blocker.
1991,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Fedida,
Gating charge and ionic currents associated with quinidine block of human Kv1.5 delayed rectifier channels.
1997,
Pubmed
Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase
HODGKIN,
A quantitative description of membrane current and its application to conduction and excitation in nerve.
1952,
Pubmed
Holmgren,
Trapping of organic blockers by closing of voltage-dependent K+ channels: evidence for a trap door mechanism of activation gating.
1997,
Pubmed
Hoshi,
Biophysical and molecular mechanisms of Shaker potassium channel inactivation.
1990,
Pubmed
,
Xenbase
Hoshi,
Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.
1991,
Pubmed
,
Xenbase
Imaizumi,
Quinidine-induced inhibition of transient outward current in cardiac muscle.
1987,
Pubmed
Li,
Regulation of N- and C-type inactivation of Kv1.4 by pHo and K+: evidence for transmembrane communication.
2003,
Pubmed
,
Xenbase
Liu,
Dynamic rearrangement of the outer mouth of a K+ channel during gating.
1996,
Pubmed
López-Barneo,
Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels.
1993,
Pubmed
,
Xenbase
McKinnon,
Molecular identity of Ito: Kv1.4 redux.
1999,
Pubmed
Molina,
Pore mutations in Shaker K+ channels distinguish between the sites of tetraethylammonium blockade and C-type inactivation.
1997,
Pubmed
Nerbonne,
Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium.
2000,
Pubmed
Rasmusson,
Bi-stable block by 4-aminopyridine of a transient K+ channel (Kv1.4) cloned from ferret ventricle and expressed in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Rasmusson,
C-type inactivation controls recovery in a fast inactivating cardiac K+ channel (Kv1.4) expressed in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Rasmusson,
Inactivation of voltage-gated cardiac K+ channels.
1998,
Pubmed
Slawsky,
K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes.
1994,
Pubmed
Snyders,
Time-, voltage-, and state-dependent block by quinidine of a cloned human cardiac potassium channel.
1992,
Pubmed
Snyders,
Determinants of antiarrhythmic drug action. Electrostatic and hydrophobic components of block of the human cardiac hKv1.5 channel.
1995,
Pubmed
Starmer,
Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics.
1984,
Pubmed
Todt,
Ultra-slow inactivation in mu1 Na+ channels is produced by a structural rearrangement of the outer vestibule.
1999,
Pubmed
,
Xenbase
Tseng,
Molecular structure of cardiac Ito channels: Kv4.2, Kv4.3, and other possibilities?
1999,
Pubmed
Wang,
A mutation in segment I-S6 alters slow inactivation of sodium channels.
1997,
Pubmed
Wang,
Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation.
1997,
Pubmed
,
Xenbase
Wang,
Potential molecular basis of different physiological properties of the transient outward K+ current in rabbit and human atrial myocytes.
1999,
Pubmed
,
Xenbase
Wickenden,
Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle.
1999,
Pubmed
Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed
Yang,
Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence.
1996,
Pubmed
Yang,
Inhibition of cardiac potassium currents by the vesnarinone analog OPC-18790: comparison with quinidine and dofetilide.
1997,
Pubmed
Yatani,
Block of transient outward-type cloned cardiac K+ channel currents by quinidine.
1993,
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
Yeola,
Electrophysiological and pharmacological correspondence between Kv4.2 current and rat cardiac transient outward current.
1997,
Pubmed
Zagotta,
Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB.
1990,
Pubmed
,
Xenbase
Zhang,
Molecular determinants of voltage-dependent inactivation in calcium channels.
1994,
Pubmed
,
Xenbase
Zhang,
Differential effects of S6 mutations on binding of quinidine and 4-aminopyridine to rat isoform of Kv1.4: common site but different factors in determining blockers' binding affinity.
1998,
Pubmed
,
Xenbase
