Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6954
pubmed:dateCreated
2003-9-11
pubmed:databankReference
pubmed:abstractText
The family of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels are crucial for a range of electrical signalling, including cardiac and neuronal pacemaker activity, setting resting membrane electrical properties and dendritic integration. These nonselective cation channels, underlying the I(f), I(h) and I(q) currents of heart and nerve cells, are activated by membrane hyperpolarization and modulated by the binding of cyclic nucleotides such as cAMP and cGMP. The cAMP-mediated enhancement of channel activity is largely responsible for the increase in heart rate caused by beta-adrenergic agonists. Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore. X-ray crystallographic structures of this C-terminal fragment bound to cAMP or cGMP, together with equilibrium sedimentation analysis, identify a tetramerization domain and the mechanism for cyclic nucleotide specificity, and suggest a model for ligand-dependent channel modulation. On the basis of amino acid sequence similarity to HCN channels, the cyclic nucleotide-gated, and eag- and KAT1-related families of channels are probably related to HCN channels in structure and mechanism.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1476-4687
pubmed:author
pubmed:issnType
Electronic
pubmed:day
11
pubmed:volume
425
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
200-5
pubmed:dateRevised
2011-3-9
pubmed:meshHeading
pubmed-meshheading:12968185-Amino Acid Sequence, pubmed-meshheading:12968185-Animals, pubmed-meshheading:12968185-Binding Sites, pubmed-meshheading:12968185-Cyclic AMP, pubmed-meshheading:12968185-Cyclic GMP, pubmed-meshheading:12968185-Cyclic Nucleotide-Gated Cation Channels, pubmed-meshheading:12968185-Electric Conductivity, pubmed-meshheading:12968185-Hydrogen Bonding, pubmed-meshheading:12968185-Ion Channel Gating, pubmed-meshheading:12968185-Ion Channels, pubmed-meshheading:12968185-Ligands, pubmed-meshheading:12968185-Mice, pubmed-meshheading:12968185-Models, Molecular, pubmed-meshheading:12968185-Molecular Sequence Data, pubmed-meshheading:12968185-Nerve Tissue Proteins, pubmed-meshheading:12968185-Patch-Clamp Techniques, pubmed-meshheading:12968185-Potassium Channels, pubmed-meshheading:12968185-Protein Conformation, pubmed-meshheading:12968185-Protein Subunits, pubmed-meshheading:12968185-Structure-Activity Relationship, pubmed-meshheading:12968185-Substrate Specificity
pubmed:year
2003
pubmed:articleTitle
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
pubmed:affiliation
Department 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
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.