Bipolar switching by HCN voltage sensor underlies hyperpolarization activation.

Abstract:

:Despite sharing a common architecture with archetypal voltage-gated ion channels (VGICs), hyperpolarization- and cAMP-activated ion (HCN) channels open upon hyperpolarization rather than depolarization. The basic motions of the voltage sensor and pore gates are conserved, implying that these domains are inversely coupled in HCN channels. Using structure-guided protein engineering, we systematically assembled an array of mosaic channels that display the full complement of voltage-activation phenotypes observed in the VGIC superfamily. Our studies reveal that the voltage sensor of the HCN channel has an intrinsic ability to drive pore opening in either direction and that the extra length of the HCN S4 is not the primary determinant for hyperpolarization activation. Tight interactions at the HCN voltage sensor-pore interface drive the channel into an hERG-like inactivated state, thereby obscuring its opening upon depolarization. This structural element in synergy with the HCN cyclic nucleotide-binding domain and specific interactions near the pore gate biases the channel toward hyperpolarization-dependent opening. Our findings reveal an unexpected common principle underpinning voltage gating in the VGIC superfamily and identify the essential determinants of gating polarity.

authors

Cowgill J,Klenchin VA,Alvarez-Baron C,Tewari D,Blair A,Chanda B

doi

10.1073/pnas.1816724116

subject

Has Abstract

pub_date

2019-01-08 00:00:00

pages

670-678

issue

2

eissn

0027-8424

issn

1091-6490

pii

1816724116

journal_volume

116

pub_type

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