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Cardiac HCN channels: structure, function, and modulation
Martin Biel1, Angela Schneider, Christian Wahl
1Department of Pharmazie-Zentrum Für Pharmaforschung, Ludwig-Maximilians-Universität, Müchen, Germany. mbiel@cup.uni-muenchen.de
Insights
The hyperpolarization-activated cation current (I(f)) is generated by HCN channels, crucial for pacemaker activity. This review explores HCN channel diversity, structure, and function in the heart.
Area of Science:
- Cardiovascular Physiology
- Neuroscience
- Molecular Biology
Background:
- The hyperpolarization-activated cation current (I(f)) is vital for pacemaker activity in cardiac and neuronal cells.
- The molecular basis of I(f) remained elusive until the identification of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family.
Purpose of the Study:
- To review the molecular and functional diversity of the HCN channel family.
- To explore the structural determinants of HCN channel function.
- To examine HCN channel expression in the heart and relate cloned HCN types to native I(f).
Main Methods:
- Molecular cloning of HCN subunits (HCN1-4).
- Heterologous expression of HCN channels.
- Biophysical characterization of expressed channels.
- Review of existing literature on HCN channel structure, function, and expression.
Main Results:
- Each of the four HCN subunits (HCN1-4) generates channels exhibiting properties of native I(f).
- HCN channels are confirmed as the molecular correlate of the cardiac I(f) current.
- Significant molecular and functional diversity exists within the HCN channel family.
Conclusions:
- HCN channels are the molecular basis for the crucial I(f) current.
- Understanding HCN channel diversity is key to comprehending cardiac and neuronal pacemaking.
- Further research into HCN channel structure-function relationships will illuminate their roles in cardiac physiology.
Abstract:
The hyperpolarization-activated cation current (termed I(f), I(h), or I(q)) plays a key role in the initiation and modulation of cardiac and neuronal pacemaker depolarizations. Recently, the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of ion channel subunits has been identified by molecular cloning. When heterologously expressed, each of the four HCN subunits (HCN1-4) generates channels with the principal properties of native I(f), indicating that HCN channels are the molecular correlate of this current. This review describes the molecular and functional diversity of the HCN channel family. The structural determinants of channel activation, modulation, and ion permeation are discussed. The expression pattern of HCN channels in different heart regions is reviewed. Finally, the relationships between biophysical properties of cloned HCN channel types and native cardiac I(f) are explored.