Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2011 Dec 30;28652:44811-20. doi: 10.1074/jbc.M111.297606.
Show Gene links
Show Anatomy links
Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
Lolicato M
,
Nardini M
,
Gazzarrini S
,
Möller S
,
Bertinetti D
,
Herberg FW
,
Bolognesi M
,
Martin H
,
Fasolini M
,
Bertrand JA
,
Arrigoni C
,
Thiel G
,
Moroni A
.
???displayArticle.abstract???
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP; binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV but shifts that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1, we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C-linker plus CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations, whereas those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V(½) in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels.
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001, Pubmed
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001,
Pubmed
Barbuti,
Action of internal pronase on the f-channel kinetics in the rabbit SA node.
1999,
Pubmed
Chen,
Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide.
2001,
Pubmed
,
Xenbase
DiFrancesco,
Pacemaker mechanisms in cardiac tissue.
1993,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Evans,
Scaling and assessment of data quality.
2006,
Pubmed
García De La Torre,
Calculation of hydrodynamic properties of globular proteins from their atomic-level structure.
2000,
Pubmed
Gauss,
Molecular identification of a hyperpolarization-activated channel in sea urchin sperm.
1998,
Pubmed
Kang,
Small potassium ion channel proteins encoded by chlorella viruses.
2004,
Pubmed
,
Xenbase
Kusch,
Interdependence of receptor activation and ligand binding in HCN2 pacemaker channels.
2010,
Pubmed
,
Xenbase
Leslie,
The integration of macromolecular diffraction data.
2006,
Pubmed
Ludwig,
A family of hyperpolarization-activated mammalian cation channels.
1998,
Pubmed
Moll,
Biomolecular interaction analysis in functional proteomics.
2006,
Pubmed
Moll,
Comparative thermodynamic analysis of cyclic nucleotide binding to protein kinase A.
2007,
Pubmed
Murshudov,
Refinement of macromolecular structures by the maximum-likelihood method.
1997,
Pubmed
Robinson,
Hyperpolarization-activated cation currents: from molecules to physiological function.
2003,
Pubmed
Santoro,
The multiple personalities of h-channels.
2003,
Pubmed
Santoro,
Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain.
1998,
Pubmed
,
Xenbase
Schuck,
Size-distribution analysis of proteins by analytical ultracentrifugation: strategies and application to model systems.
2002,
Pubmed
Scott,
Mapping ligand interactions with the hyperpolarization activated cyclic nucleotide modulated (HCN) ion channel binding domain using a soluble construct.
2007,
Pubmed
Taraska,
Mapping the structure and conformational movements of proteins with transition metal ion FRET.
2009,
Pubmed
Ulens,
Regulation of hyperpolarization-activated HCN channels by cAMP through a gating switch in binding domain symmetry.
2003,
Pubmed
,
Xenbase
Vagin,
Molecular replacement with MOLREP.
2010,
Pubmed
Wainger,
Molecular mechanism of cAMP modulation of HCN pacemaker channels.
2001,
Pubmed
Wang,
Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
2002,
Pubmed
,
Xenbase
Wang,
Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions.
2001,
Pubmed
,
Xenbase
Weber,
Structure of a complex of catabolite gene activator protein and cyclic AMP refined at 2.5 A resolution.
1987,
Pubmed
Wicks,
Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating.
2011,
Pubmed
,
Xenbase
Wiseman,
Rapid measurement of binding constants and heats of binding using a new titration calorimeter.
1989,
Pubmed
Wu,
State-dependent cAMP binding to functioning HCN channels studied by patch-clamp fluorometry.
2011,
Pubmed
Xu,
Structural basis for the cAMP-dependent gating in the human HCN4 channel.
2010,
Pubmed
,
Xenbase
Zagotta,
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
2003,
Pubmed
Zhou,
Gating of HCN channels by cyclic nucleotides: residue contacts that underlie ligand binding, selectivity, and efficacy.
2007,
Pubmed
,
Xenbase
Zhou,
A conserved tripeptide in CNG and HCN channels regulates ligand gating by controlling C-terminal oligomerization.
2004,
Pubmed
,
Xenbase
