Structures of the Human HCN1 Hyperpolarization-Activated Channel

Area of Science:

• Biophysics
• Molecular Biology
• Structural Biology

Background:

• Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate rhythmic activity in cardiac and neuronal pacemaker cells.
• HCN channels exhibit reversed polarity of voltage dependence, modulated by intracellular cyclic adenosine monophosphate (cAMP).

Purpose of the Study:

• To determine the high-resolution structures of human HCN channels.
• To elucidate the mechanisms of unique ion selectivity, reversed voltage gating, and cAMP-mediated regulation.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to obtain structures of the human HCN channel.
• Structures were determined in both the absence and presence of cAMP at 3.5 Å resolution.

Main Results:

• The structures reveal a unique K+-channel selectivity filter-forming sequence responsible for Na+ and K+ permeability.
• The voltage sensor is in a depolarized conformation with the pore closed, featuring an extended S4 helix that gates the pore.
• cAMP binding induces conformational changes in cytoplasmic domains, promoting pore opening.

Conclusions:

• These structures provide unprecedented insight into the molecular basis of HCN channel function.
• The findings advance understanding of ion selectivity, reversed gating polarity, and cAMP's role in regulating cardiac and neuronal pacemaking.