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J. Biol. Chem., Vol. 280, Issue 29, 27056-27061, July 22, 2005

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The Murine HCN3 Gene Encodes a Hyperpolarization-activated Cation Channel with Slow Kinetics and Unique Response to Cyclic Nucleotides^*

Pavel Mistrík, Robert Mader, Stylianos Michalakis, Martha Weidinger, Alexander Pfeifer, and Martin Biel

From the Department of Pharmazie, Pharmakologie für Naturwissenschaften, Ludwig-Maximilians Universität München, Butenandtstr. 7, 81377 München, Germany

Hyperpolarization-activated cation channels of the HCN gene family are crucial for the regulation of cell excitability. Importantly, these channels play a pivotal role in the control of cardiac and neuronal pacemaker activity. Dysfunction of HCN channels has been associated with human diseases, including cardiac arrhythmia, epilepsy, and neuropathic pain. The properties of three HCN channel isoforms (HCN1, HCN2, and HCN4) have been extensively investigated. By contrast, due to the lack of an efficient heterologous expression system, the functional characteristics of HCN3 were by and large unknown so far. Here, we have used lentiviral gene transfer to overexpress HCN3 in HEK293T cells. HCN3 currents revealed slow activation and deactivation kinetics and were effectively blocked by extracellular Cs⁺ and the bradycardic agent ivabradine. Cyclic AMP and cGMP had no significant impact on activation kinetics but induced a 5-mV shift of the half-maximal activation voltage (V_0.5) to more hyperpolarized potentials. A negative shift of V_0.5 induced by cyclic nucleotides is an unprecedented feature within the HCN channel family. The expression of HCN3 in mouse brain was examined by Western blot analysis using a specific antibody. High levels of protein were detected in olfactory bulb and hypothalamus. In contrast, only very low expression was found in cortex. Using reverse transcriptase PCR transcripts of HCN3 were also detected in heart ventricle. In conclusion, the distinct expression pattern in conjunction with the unusual biophysical properties implies that HCN3 may play an unique role in the body.

Received for publication, March 11, 2005 , and in revised form, May 27, 2005.

^* This work was supported by the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 49-89-2180-77327; Fax: 49-89-2180-77326; E-mail: mbiel{at}cup.uni-muenchen.de.

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