| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CELLULAR |
Center for Cellular and Systems Electrophysiology,
1 Department of Gynecology and Obstetrics
2 Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, 124 Sherman Hall, State University of New York at Buffalo, Buffalo, NY 14214-3005, USA
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 (IC50 for KCNQ1 = 65.4 ± 1.7 µM; KCNQ1/KCNE1 = 15.1 ± 3.3 µM; KCNQ1/KCNE3 = 0.54 ± 0.18 µM). 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.
(Received 26 June 2006;
accepted after revision 3 August 2006;
first published online 3 August 2006)
Corresponding author G. C. L. Bett: Department of Gynecology and Obstetrics, Department of Physiology and Biophysics, 124 Sherman Hall, State University of NY at Buffalo, Buffalo, NY 14214, USA. Email: bett{at}buffalo.edu
This article has been cited by other articles:
|
|
 |
|
  Z. Gao, Q. Xiong, H. Sun, and M. Li Desensitization of Chemical Activation by Auxiliary Subunits: CONVERGENCE OF MOLECULAR DETERMINANTS CRITICAL FOR AUGMENTING KCNQ1 POTASSIUM CHANNELS J. Biol. Chem., August 15, 2008; 283(33): 22649 - 22658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. L. Bett and R. L. Rasmusson Modification of K+ channel-drug interactions by ancillary subunits J. Physiol., February 15, 2008; 586(4): 929 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Rocheleau and W. R. Kobertz KCNE Peptides Differently Affect Voltage Sensor Equilibrium and Equilibration Rates in KCNQ1 K+ Channels J. Gen. Physiol., December 31, 2007; 131(1): 59 - 68. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
