[PDF][PDF] Structures of the human HCN1 hyperpolarization-activated channel

CH Lee, R MacKinnon - Cell, 2017 - cell.com
CH Lee, R MacKinnon
Cell, 2017cell.com
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the control of
rhythmic activity in cardiac and neuronal pacemaker cells. In HCN, the polarity of voltage
dependence is uniquely reversed. Intracellular cyclic adenosine monophosphate (cAMP)
levels tune the voltage response, enabling sympathetic nerve stimulation to increase the
heart rate. We present cryo-electron microscopy structures of the human HCN channel in the
absence and presence of cAMP at 3.5 Å resolution. HCN channels contain a K+ channel …
Summary
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the control of rhythmic activity in cardiac and neuronal pacemaker cells. In HCN, the polarity of voltage dependence is uniquely reversed. Intracellular cyclic adenosine monophosphate (cAMP) levels tune the voltage response, enabling sympathetic nerve stimulation to increase the heart rate. We present cryo-electron microscopy structures of the human HCN channel in the absence and presence of cAMP at 3.5 Å resolution. HCN channels contain a K+ channel selectivity filter-forming sequence from which the amino acids create a unique structure that explains Na+ and K+ permeability. The voltage sensor adopts a depolarized conformation, and the pore is closed. An S4 helix of unprecedented length extends into the cytoplasm, contacts the C-linker, and twists the inner helical gate shut. cAMP binding rotates cytoplasmic domains to favor opening of the inner helical gate. These structures advance understanding of ion selectivity, reversed polarity gating, and cAMP regulation in HCN channels.
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