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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/H355    most recent 00154.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Brandt, M. C. Articles by Hoppe, U. C. PubMed PubMed Citation Articles by Brandt, M. C. Articles by Hoppe, U. C.

Effects of KCNE2 on HCN isoforms: distinct modulation of membrane expression and single channel properties

¹Department of Internal Medicine III and ²Center for Molecular Medicine, University of Cologne, Cologne, Germany

Submitted 17 February 2009 ; accepted in final form 30 April 2009

Hyperpolarization-activated cation (HCN) channels give rise to an inward current with similar but not identical characteristics compared with the pacemaker current (I_f), suggesting that HCN channel function is modulated by regulatory β-subunits in native tissue. KCNE2 has been proposed to serve as a β-subunit of HCN channels; however, available data remain contradictory. To further clarify this situation, we therefore analyzed the effect of KCNE2 on whole cell currents, single channel properties, and membrane protein expression of all cardiac HCN isoforms in the CHO cell system. On the whole cell level, current densities of all HCN isoforms were significantly increased by KCNE2 without altering voltage dependence or current reversal. While these results correlated well with the KCNE2-mediated 2.2-fold and 1.6-fold increases of membrane protein levels of HCN2 and HCN4, respectively, no effect of KCNE2 on HCN1 expression was obtained. All HCN subtypes displayed faster activation kinetics upon coexpression with KCNE2. Most importantly, for the first time, we demonstrated modulation of single channel function by KCNE2, thus supporting direct functional interaction with HCN subunits. In the presence of KCNE2, the single channel amplitudes and conductance of HCN1, HCN2, and HCN4 were significantly increased versus control recordings. Mean open time was significantly increased in cells coexpressing HCN2 + KCNE2, whereas it was unaffected in HCN1 + KCNE2 cotransfected cells and reduced in HCN4 + KCNE2 cotransfected cells compared with the respective HCN subunits alone. Thus, we demonstrate KCNE2-mediated distinct effects on HCN membrane expression and direct functional modulation of HCN isoforms, further supporting that KCNE2 surves as a regulatory β-subunit of HCN channels.

pacemaker current; hyperpolarization-activated cation; MinK-related peptide; electrophysiology