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| | ==Structure of the cyclic nucleotide-binding domain of HCN4 channel complexed with 7-CH-cAMP== | | ==Structure of the cyclic nucleotide-binding domain of HCN4 channel complexed with 7-CH-cAMP== |
| - | <StructureSection load='4nvp' size='340' side='right' caption='[[4nvp]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='4nvp' size='340' side='right'caption='[[4nvp]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4nvp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NVP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NVP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4nvp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NVP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NVP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7CH:(2S,4AR,6R,7R,7AS)-6-(4-AMINO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)TETRAHYDRO-4H-FURO[3,2-D][1,3,2]DIOXAPHOSPHININE-2,7-DIOL+2-OXIDE'>7CH</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7CH:(2S,4AR,6R,7R,7AS)-6-(4-AMINO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)TETRAHYDRO-4H-FURO[3,2-D][1,3,2]DIOXAPHOSPHININE-2,7-DIOL+2-OXIDE'>7CH</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3u11|3u11]], [[3otf|3otf]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4nvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nvp OCA], [https://pdbe.org/4nvp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nvp RCSB], [https://www.ebi.ac.uk/pdbsum/4nvp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nvp ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HCN4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nvp OCA], [http://pdbe.org/4nvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nvp RCSB], [http://www.ebi.ac.uk/pdbsum/4nvp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nvp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/HCN4_HUMAN HCN4_HUMAN]] Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:[http://omim.org/entry/163800 163800]]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:16407510</ref> <ref>PMID:20662977</ref> Brugada syndrome 8 (BRGDA8) [MIM:[http://omim.org/entry/613123 613123]]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19165230</ref> | + | [https://www.uniprot.org/uniprot/HCN4_HUMAN HCN4_HUMAN] Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:[https://omim.org/entry/163800 163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:16407510</ref> <ref>PMID:20662977</ref> Brugada syndrome 8 (BRGDA8) [MIM:[https://omim.org/entry/613123 613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19165230</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HCN4_HUMAN HCN4_HUMAN]] Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.<ref>PMID:10228147</ref> <ref>PMID:10430953</ref> | + | [https://www.uniprot.org/uniprot/HCN4_HUMAN HCN4_HUMAN] Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.<ref>PMID:10228147</ref> <ref>PMID:10430953</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Ion channels|Ion channels]] | + | *[[Ion channels 3D structures|Ion channels 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Alfieri, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Moroni, A]] | + | [[Category: Alfieri A]] |
| - | [[Category: Cyclic nucleotide binding domain]] | + | [[Category: Moroni A]] |
| - | [[Category: Cytoplasmic domain]]
| + | |
| - | [[Category: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Disease
HCN4_HUMAN Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:163800: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] Brugada syndrome 8 (BRGDA8) [MIM:613123: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.[3]
Function
HCN4_HUMAN Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.[4] [5]
Publication Abstract from PubMed
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a central role in the regulation of cardiac and neuronal firing rate, and these channels can be dually activated by membrane hyperpolarization and by binding of cyclic nucleotides. cAMP has been shown to directly bind HCN channels and modulate their activity. Despite this, while there are selective inhibitors that block the activation potential of the HCN channels, regulation by cAMP analogs has not been well investigated. A comprehensive screen of 47 cyclic nucleotides with modifications in the nucleobase, ribose moiety, and cyclic phosphate was tested on the three isoforms HCN1, HCN2, and HCN4. 7-CH-cAMP was identified to be a high affinity binder for HCN channels and crosschecked for its ability to act on other cAMP receptor proteins. While 7-CH-cAMP is a general activator for cAMP- and cGMP-dependent protein kinases as well as for the guanine nucleotide exchange factors Epac1 and Epac2, it displays the highest affinity to HCN channels. The molecular basis of the high affinity was investigated by determining the crystal structure of 7-CH-cAMP in complex with the cyclic nucleotide binding domain of HCN4. Electrophysiological studies demonstrate a strong activation potential of 7-CH-cAMP for the HCN4 channel in vivo. So, this makes 7-CH-cAMP a promising activator of the HCN channels in vitro whose functionality can be translated in living cells.
Cyclic Nucleotide Mapping of Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels.,Moller S, Alfieri A, Bertinetti D, Aquila M, Schwede F, Lolicato M, Rehmann H, Moroni A, Herberg FW ACS Chem Biol. 2014 May 16;9(5):1128-37. doi: 10.1021/cb400904s. Epub 2014 Mar 7. PMID:24605759[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006 Jan 12;354(2):151-7. PMID:16407510 doi:10.1056/NEJMoa052475
- ↑ Laish-Farkash A, Glikson M, Brass D, Marek-Yagel D, Pras E, Dascal N, Antzelevitch C, Nof E, Reznik H, Eldar M, Luria D. A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol. 2010 Dec;21(12):1365-72. doi:, 10.1111/j.1540-8167.2010.01844.x. PMID:20662977 doi:10.1111/j.1540-8167.2010.01844.x
- ↑ Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009 Feb;54(2):115-21. doi: 10.1038/jhg.2008.16. Epub 2009 Jan 23. PMID:19165230 doi:10.1038/jhg.2008.16
- ↑ Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 1999 May 4;18(9):2323-9. PMID:10228147 doi:10.1093/emboj/18.9.2323
- ↑ Seifert R, Scholten A, Gauss R, Mincheva A, Lichter P, Kaupp UB. Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9391-6. PMID:10430953
- ↑ Moller S, Alfieri A, Bertinetti D, Aquila M, Schwede F, Lolicato M, Rehmann H, Moroni A, Herberg FW. Cyclic Nucleotide Mapping of Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels. ACS Chem Biol. 2014 May 16;9(5):1128-37. doi: 10.1021/cb400904s. Epub 2014 Mar 7. PMID:24605759 doi:http://dx.doi.org/10.1021/cb400904s
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