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Gating movements and ion permeation in HCN4 pacemaker channels. 2021
Andrea Saponaro, and
Daniel Bauer, and
M Hunter Giese, and
Paolo Swuec, and
Alessandro Porro, and
Federica Gasparri, and
Atiyeh Sadat Sharifzadeh, and
Antonio Chaves-Sanjuan, and
Laura Alberio, and
Giacomo Parisi, and
Gabriele Cerutti, and
Oliver B Clarke, and
Kay Hamacher, and
Henry M Colecraft, and
Filippo Mancia, and
Wayne A Hendrickson, and
Steven A Siegelbaum, and
Dario DiFrancesco, and
Martino Bolognesi, and
Gerhard Thiel, and
Bina Santoro, and
Anna Moroni
Department of Biosciences, University of Milan, Milan, Italy.
The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. We present cryoelectron microscopy (cryo-EM) structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures sheds light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlights the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation. Our results contribute mechanistic understanding on HCN channel gating, cyclic nucleotide-dependent modulation, and ion permeation.
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