Title: Regulation of hyperpolarization-activated HCN channels by cAMP through a gating switch in binding domain symmetry
Authors: Ulens, Chris
Siegelbaum, SA # ×
Issue Date: Dec-2003
Publisher: Cell press
Series Title: Neuron vol:40 issue:5 pages:959-970
Abstract: Recent X-ray structures show that the binding domains of tetrameric ligand-gated channels form either a 4-fold symmetric gating ring or a 2-fold symmetric dimer of dimers. To determine how such structures function to coordinate the binding of multiple ligands during channel activation, we examined the action of cAMP to enhance the opening of the hyperpolarization-activated HCN2 channels, whose cytoplasmic C terminus forms a gating ring in the presence of cAMP. Using tandem dimers and tetramers; in which cAMP binding to selected HCN2 subunits was prevented by a point mutation or deletion, we provide the first direct determination of the energetic effects on gating of each of four ligand binding events and demonstrate the importance of the gating ring for cAMP regulation. We suggest that cAMP binding enhances channel opening by promoting assembly of the gating ring from an unliganded state in which the four subunits interact as a 2-fold symmetric dimer of dimers.
ISSN: 0896-6273
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Structural Neurobiology
× corresponding author
# (joint) last author

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