The Journal of General Physiology
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Published online
doi:10.1085/jgp.200709769
The Journal of General Physiology, Vol. 130, No. 1, 71-81
The Rockefeller University Press, 0022-1295 $30.00
© Bruening-Wright et al.
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ARTICLE

 Kinetic Relationship between the Voltage Sensor and the Activation Gate in spHCN Channels



Andrew Bruening-Wright1, Fredrik Elinder2, and H. Peter Larsson1

1 Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006
2 Department of Biomedicine and Surgery, Division of Cell Biology, Linköpings Universitet, SE-581 85 Linköping, Sweden

Correspondence to H. Peter Larsson: larssonp{at}ohsu.edu

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by membrane hyperpolarizations that cause an inward movement of the positive charges in the fourth transmembrane domain (S4), which triggers channel opening. The mechanism of how the motion of S4 charges triggers channel opening is unknown. Here, we used voltage clamp fluorometry (VCF) to detect S4 conformational changes and to correlate these to the different activation steps in spHCN channels. We show that S4 undergoes two distinct conformational changes during voltage activation. Analysis of the fluorescence signals suggests that the N-terminal region of S4 undergoes conformational changes during a previously characterized mode shift in HCN channel voltage dependence, while a more C-terminal region undergoes an additional conformational change during gating charge movements. We fit our fluorescence and ionic current data to a previously proposed 10-state allosteric model for HCN channels. Our results are not compatible with a fast S4 motion and rate-limiting channel opening. Instead, our data and modeling suggest that spHCN channels open after only two S4s have moved and that S4 motion is rate limiting during voltage activation of spHCN channels.

Abbreviations used in this paper: HCN, hyperpolarization-activated cyclic nucleotide-gated; S4, fourth transmembrane domain; VCF, voltage clamp fluorometry.


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