The Journal of General Physiology
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Published online 14 August 2006 doi:10.1085/jgp.200609590
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 128, Number 3, 273-282
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ARTICLE

 Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6



David L. Prole and Gary Yellen

Department of Neurobiology, Harvard Medical School, Boston, MA 02115

Correspondence to Gary Yellen: gary_yellen{at}hms.harvard.edu

Voltage-gated ion channels possess charged domains that move in response to changes in transmembrane voltage. How this movement is transduced into gating of the channel pore is largely unknown. Here we show directly that two functionally important regions of the spHCN1 pacemaker channel, the S4–S5 linker and the C-linker, come into close proximity during gating. Cross-linking these regions with high-affinity metal bridges or disulfide bridges dramatically alters channel gating in the absence of cAMP; after modification the polarity of voltage dependence is reversed. Instead of being closed at positive voltage and activating with hyperpolarization, modified channels are closed at negative voltage and activate with depolarization. Mechanistically, this reversal of voltage dependence occurs as a result of selectively eliminating channel deactivation, while retaining an existing inactivation process. Bridging also alters channel activation by cAMP, showing that interaction of these two regions can also affect the efficacy of physiological ligands.

Abbreviations used in this paper: DTDP, 2-2'-dithiodipyridine; DTNB, 5,5'-dithiobis(2-nitrobenzoic acid); DTT, dithiothreitol.


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