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Hypoosmotic Cell Swelling as a Novel Mechanism for Modulation of Cloned HCN2 Channels

Kirstine Calloe ^*, Pernille Elmedyb ^*, Soren-Peter Olesen ^* , Nanna K. Jorgensen ^* and Morten Grunnet ^* 

^* Copenhagen Heart Arrhythmia Research Centre and Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and NeuroSearch, Ballerup, Denmark

Correspondence: Address reprint requests to Kirstine Calloe, Dept. of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: kirstinec{at}mfi.ku.dk.

This work demonstrates cell swelling as a new regulatory mechanism for the cloned hyperpolarization-activated, cyclic nucleotide-gated channel 2 (HCN2). HCN2 channels were coexpressed with aquaporin1 in Xenopus laevis oocytes and currents were monitored using a two-electrode voltage-clamp. HCN2 channels were activated by hyperpolarization to –100 mV and the currents were measured before and during hypoosmotic cell swelling. Cell swelling increased HCN2 currents by 30% without changing the kinetics of the currents. Injection of 50 nl intracellular solution resulted in a current increase of 20%, indicating that an increase in cell volume also under isoosmotic conditions may lead to activation of HCN2. In the absence of aquaporin1 only negligible changes in oocyte cell volume occur during exposure to hypoosmotic media and no significant change in HCN2 channel activity was observed during perfusion with hypoosmotic media. This indicates that cell swelling and not a change in ionic strength of the media, caused the observed swelling-induced increase in current. The increase in HCN2 current induced by cell swelling could be abolished by cytochalasin D treatment, indicating that an intact F-actin cytoskeleton is a prerequisite for the swelling-induced current.

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