Structural basis for modulation and agonist specificity of HCN pacemaker channels.
William N Zagotta1, Nelson B Olivier, Kevin D Black
1Department of Physiology and Biophysics, Howard Hughes Medical Institute, Box 357290, University of Washington School of Medicine, Seattle, Washington 98195-7290, USA. zagotta@u.washington.edu
Nature
|September 12, 2003
Summary
Researchers explored how cyclic nucleotides modulate hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels. Understanding this mechanism reveals insights into cardiac and neuronal electrical signaling and potential drug targets.
Area of Science:
- Molecular Biology
- Biophysics
- Neuroscience
Background:
- Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels are vital for electrical signaling in the heart and brain.
- These channels control pacemaker activity and neuronal integration, influenced by cyclic nucleotides like cAMP and cGMP.
- cAMP significantly enhances HCN channel activity, contributing to increased heart rate via beta-adrenergic agonists.
Purpose of the Study:
- To elucidate the molecular mechanism of cyclic nucleotide modulation in HCN channels.
- To investigate the structural basis of cyclic nucleotide specificity in HCN channel function.
Main Methods:
- X-ray crystallography was used to determine the structures of an HCN2 channel C-terminal fragment bound to cAMP or cGMP.
- Equilibrium sedimentation analysis was employed to study the oligomeric state and interactions within the channel fragment.
Main Results:
- The study identified a tetramerization domain within the C-terminal fragment of HCN2.
- Structural and biochemical data revealed the mechanism underlying the specificity of cAMP and cGMP binding.
- A model for ligand-dependent modulation of HCN channel activity was proposed.
Conclusions:
- The findings provide a structural basis for understanding how cyclic nucleotides regulate HCN channel function.
- The identified tetramerization domain and binding mechanism are crucial for channel gating and modulation.
- Structural similarities suggest related mechanisms in other cyclic nucleotide-gated and related ion channel families.
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