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J Physiol Volume 586, Number 3, 701-716, February 1, 2008 DOI: 10.1113/jphysiol.2007.144329
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Cellular

Hyperpolarization-activated cyclic nucleotide-modulated ‘HCN’ channels confer regular and faster rhythmicity to beating mouse embryonic stem cells

 Yang Qu1,2, Gina M. Whitaker3, Leif Hove-Madsen4, Glen F. Tibbits1,2 and Eric A. Accili3

1 Cardiac Membrane Research Laboratory, Simon Fraser University, Burnaby, BC, Canada
2 Cardiovascular Sciences, Child and Family Research Institute, Vancouver, BC, Canada
3 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
4 Laboratorio de Fisiologia Celular, Servei de Cardiologia, Hospital de Sant Pau, 08025 Barcelona, Spain

The hyperpolarization-activated cation current (If), and the hyperpolarization-activated cyclic nucleotide-modulated ‘HCN’ subunits that underlie it, are important components of spontaneous activity in the embryonic mouse heart, but whether they contribute to this activity in mouse embryonic stem cell-derived cardiomyocytes has not been investigated. We address this issue in spontaneously beating cells derived from mouse embryonic stem cells (mESCs) over the course of development in culture. If and action potentials were recorded from single beating cells at early, intermediate and late development stages using perforated whole-cell voltage- and current-clamp techniques. Our data show that the proportion of cells expressing If, and the density of If in these cells, increased during development and correlated with action potential frequency and the rate of diastolic depolarization. The If blocker ZD7288 (0.3 µM) reduced If and the beating rate of embryoid bodies. Taken together, the activation kinetics of If and results from Western blots are consistent with the presence of the HCN2 and HCN3 isoforms. At all stages of development, isoproterenol (isoprenaline) and acetylcholine shifted the voltage dependence of If to more positive and negative voltages, respectively, and they also increased and decreased the beating rate of embryonic cell bodies, respectively. Together, the data suggest that current through HCN2 and HCN3 channels confers regular and faster rhythmicity to mESCs, which mirrors the developing embryonic mouse heart, and contributes to modulation of rhythmicity by autonomic stimulation.

(Received 3 September 2007; accepted after revision 16 November 2007; first published online 22 November 2007)
Corresponding author E. A. Accili: Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6R 1Z3. Email: eaaccili{at}interchange.ubc.ca

L. Hove-Madsen, G. F. Tibbits and E. A. Accili are joint senior authors.




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