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Cardiovascular Research 2003 57(2):497-504; doi:10.1016/S0008-6363(02)00668-5
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Modulation of the hyperpolarization-activated current (If) by calcium and calmodulin in the guinea-pig sino-atrial node

Lauren Rigg, Paul A.D Mattick, Bronagh M Heath and Derek A Terrar*

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK

* Corresponding author. Tel.: +44-1865-271-613; fax: +44-1865-271-853. derek.terrar{at}pharm.ox.ac.uk

The aim of this study was to investigate possible regulation of the hyperpolarization-activated current (If) by cytosolic calcium in guinea-pig sino-atrial (SA) node cells. Isolated SA node cells were superfused with physiological saline solution (36 °C) and the perforated patch voltage-clamp technique used to record If activated by hyperpolarizing voltage steps. A 10-min loading of SA node cells with the calcium chelator BAPTA (using 10 µM BAPTA-AM) significantly reduced the amplitude of If at all potentials studied (69±8% at –80 mV, n=6). BAPTA loading also shifted the voltage of half-activation (Vh) of the conductance from –83±2 mV in control to –93±2 mV in BAPTA (n=6) without significantly altering the slope of activation. The calmodulin antagonists W-7 (10 µM), calmidazolium (25 µM) and ophiobolin A (20 µM) caused similar reductions in If amplitude (73±4, 86±9 and 59±6% at –80 mV, n=6, 5 and 4, respectively) and shifts in Vh (11±3, 14±3 and 8±2 mV). In cells pre-treated with W-7, exposure to BAPTA caused no further reduction in current amplitude (n=6). If current amplitude was unaffected by the calmodulin dependent kinase (CaMKII) inhibitor KN-93 (1 µM) although this CaMKII inhibition did reduce L-type calcium by 48±19% at 0 mV (n=3). These results are consistent with a role for calcium and calmodulin in the regulation of If, via a mechanism that is independent of CaMKII. Alterations in intracellular calcium during the cardiac cycle may be involved in fine tuning the voltage-dependent properties of If and may thus determine its relative contribution to pacemaking in the SA node.

KEYWORDS Calcium (cellular); Ion channels; Membrane currents; Sinus node


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