title: Structures of the Human HCN1 Hyperpolarization-Activated Channel.
abstract: 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.
authors.affiliation: Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Chia-Hsueh
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA. Electronic address: mackinn@rockefeller.edu.
authors.forename: Roderick
authors.initials: R
authors.lastname: MacKinnon
mesh_terms: D000595:Amino Acid Sequence; D020285:Cryoelectron Microscopy / Q000379:methods; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: C578665:HCN1 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D000242:Cyclic AMP
keywords: atomic structure; cardiac and neuronal pacemaker; cryo-electron microscopy; hyperpolarization-activated ion channel; ion selectivity; rhythmic firing; voltage-dependent gating