PMID- 14693686
OWN - NLM
STAT- MEDLINE
DCOM- 20040521
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 286
IP  - 5
DP  - 2004 May
TI  - A rapidly activating delayed rectifier K+ current regulates pacemaker activity in 
      adult mouse sinoatrial node cells.
PG  - H1757-66
AB  - We have investigated the physiological role of the "rapidly activating" delayed 
      rectifier K+ current (IKr) in pacemaker activity in isolated sinoatrial node 
      (SAN) myocytes and the expression of mouse ether-a-go-go (mERG) genes in the 
      adult mouse SAN. In isolated, voltage-clamped SAN cells, outward currents evoked 
      by depolarizing steps (greater than -40 mV) were strongly inhibited by the class 
      III methanesulfonanilide compound E-4031 (1-2.5 microM), and the deactivation 
      "tail" currents that occurred during repolarization to a membrane potential of 
      -45 mV were completely blocked. E-4031-sensitive currents (IKr) reached a maximum 
      at a membrane potential of -10 mV and showed pronounced inward rectification at 
      more-positive membrane potentials. Activation of IKr occurred at -40 to 0 mV, 
      with half-activation at about -24 mV. The contribution of IKr to action potential 
      repolarization and diastolic depolarization was estimated by determining the 
      E-4031-sensitive current evoked during voltage clamp with a simulated mouse SAN 
      action potential. IKr reached its peak value (approximately 0.6 pA/pF) near -25 
      mV, close to the midpoint of the repolarization phase of the simulated action 
      potential, and deactivated almost completely during the diastolic interval. 
      E-4031 (1 microM) slowed the spontaneous pacing rate of Langendorff-perfused, 
      isolated adult mouse hearts by an average of 36.5% (n = 5). Expression of mRNA 
      corresponding to three isoforms coded by the mouse ERG1 gene (mERG1), mERG1a, 
      mERG1a', and mERG1b, was consistently found in the SAN. Our data provide the 
      first detailed characterization of IKr in adult mouse SAN cells, demonstrate that 
      this current plays an important role in pacemaker activity, and indicate that 
      multiple isoforms of mERG1 can contribute to native SAN IKr.
FAU - Clark, Robert B
AU  - Clark RB
AD  - Department of Physiology and Biophysics, University of Calgary Health Sciences 
      Centre, Calgary, Alberta, Canada T2N 4N1. rclar@ucalgary.ca
FAU - Mangoni, Matteo E
AU  - Mangoni ME
FAU - Lueger, Andreas
AU  - Lueger A
FAU - Couette, Brigitte
AU  - Couette B
FAU - Nargeot, Joel
AU  - Nargeot J
FAU - Giles, Wayne R
AU  - Giles WR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031223
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Anti-Arrhythmia Agents)
RN  - 0 (Delayed Rectifier Potassium Channels)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (Kcnh2 protein, mouse)
RN  - 0 (Piperidines)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Protein Isoforms)
RN  - 0 (Pyridines)
RN  - 113558-89-7 (E 4031)
SB  - IM
MH  - Animals
MH  - Anti-Arrhythmia Agents/pharmacology
MH  - Biological Clocks/*physiology
MH  - Delayed Rectifier Potassium Channels
MH  - Diastole
MH  - ERG1 Potassium Channel
MH  - Electric Conductivity
MH  - Ether-A-Go-Go Potassium Channels
MH  - Female
MH  - Heart/drug effects/physiology
MH  - In Vitro Techniques
MH  - Kinetics
MH  - Male
MH  - Membrane Potentials/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Piperidines/pharmacology
MH  - Potassium Channels/metabolism/*physiology
MH  - *Potassium Channels, Voltage-Gated
MH  - Protein Isoforms/metabolism
MH  - Pyridines/pharmacology
MH  - Sinoatrial Node/cytology/drug effects/*physiology
EDAT- 2003/12/25 05:00
MHDA- 2004/05/22 05:00
CRDT- 2003/12/25 05:00
PHST- 2003/12/25 05:00 [pubmed]
PHST- 2004/05/22 05:00 [medline]
PHST- 2003/12/25 05:00 [entrez]
AID - 00753.2003 [pii]
AID - 10.1152/ajpheart.00753.2003 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2004 May;286(5):H1757-66. doi: 
      10.1152/ajpheart.00753.2003. Epub 2003 Dec 23.