Structures of the Human HCN1 Hyperpolarization-Activated Channel.
Cell
; 168(1-2): 111-120.e11, 2017 Jan 12.
Article
em En
| MEDLINE
| ID: mdl-28086084
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Potássio
/
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização
Limite:
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos