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| | <StructureSection load='5oyb' size='340' side='right' caption='[[5oyb]], [[Resolution|resolution]] 3.75Å' scene=''> | | <StructureSection load='5oyb' size='340' side='right' caption='[[5oyb]], [[Resolution|resolution]] 3.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5oyb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OYB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OYB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5oyb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OYB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OYB FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> |
| | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5oyg|5oyg]]</td></tr> | | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5oyg|5oyg]]</td></tr> |
| | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ano1, Tmem16a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=5oyb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oyb OCA], [http://pdbe.org/5oyb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oyb RCSB], [http://www.ebi.ac.uk/pdbsum/5oyb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oyb ProSAT]</span></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=5oyb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oyb OCA], [http://pdbe.org/5oyb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oyb RCSB], [http://www.ebi.ac.uk/pdbsum/5oyb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oyb ProSAT]</span></td></tr> |
| | </table> | | </table> |
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| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | Coronary vascular and myocardial responses to selective hypoxic and/or hypercapnic carotid chemoreceptor stimulation were investigated in constantly ventilated, pentobarbital or urethan-chloralose anesthetized dogs. Bilaterally isolated carotid chemoreceptors were perfused with autologous blood of varying O2 and CO2 tensions via an extracorporeal lung circuit. Systemic gas tensions were unchanged. Effects of carotid chemoreceptor stimulation on coronary vascular resistance, left ventricular dP/dt, and strain-gauge arch output were studied at natural coronary blood flow with the chest closed and during constant-flow perfusion of the left common coronary artery with the chest open. Carotid chemoreceptor stimulation slightly increased left ventricular dP/dt and slightly decreased the strain-gauge arch output, while markedly increasing systemic pressure. Coronary blood flow increased; however, coronary vascular resistance wa.as not affected. These studies show that local carotid body stimulation increases coronary blood flow but has little effect on the myocardium. The increase in coronary blood flow results mainly from an increase in systemic arterial pressure. Thus these data provide little evidence for increased sympathetic activity of the heart during local stimulation of the carotid chemoreceptors with hypoxic and hypercapnic blood.
| + | The calcium-activated chloride channel TMEM16A is a ligand-gated anion channel that opens in response to an increase in intracellular Ca(2+) concentration. The protein is broadly expressed and contributes to diverse physiological processes, including transepithelial chloride transport and the control of electrical signalling in smooth muscles and certain neurons. As a member of the TMEM16 (or anoctamin) family of membrane proteins, TMEM16A is closely related to paralogues that function as scramblases, which facilitate the bidirectional movement of lipids across membranes. The unusual functional diversity of the TMEM16 family and the relationship between two seemingly incompatible transport mechanisms has been the focus of recent investigations. Previous breakthroughs were obtained from the X-ray structure of the lipid scramblase of the fungus Nectria haematococca (nhTMEM16), and from the cryo-electron microscopy structure of mouse TMEM16A at 6.6 A (ref. 14). Although the latter structure disclosed the architectural differences that distinguish ion channels from lipid scramblases, its low resolution did not permit a detailed molecular description of the protein or provide any insight into its activation by Ca(2+). Here we describe the structures of mouse TMEM16A at high resolution in the presence and absence of Ca(2+). These structures reveal the differences between ligand-bound and ligand-free states of a calcium-activated chloride channel, and when combined with functional experiments suggest a mechanism for gating. During activation, the binding of Ca(2+) to a site located within the transmembrane domain, in the vicinity of the pore, alters the electrostatic properties of the ion conduction path and triggers a conformational rearrangement of an alpha-helix that comes into physical contact with the bound ligand, and thereby directly couples ligand binding and pore opening. Our study describes a process that is unique among channel proteins, but one that is presumably general for both functional branches of the TMEM16 family. |
| | | | |
| - | Coronary vascular and myocardial responses to carotid body stimulation in the dog.,Ehrhart IC, Parker PE, Weidner WJ, Dabney JM, Scott JB, Haddy FJ Am J Physiol. 1975 Sep;229(3):754-60. doi: 10.1152/ajplegacy.1975.229.3.754. PMID:2017<ref>PMID:2017</ref>
| + | Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM.,Paulino C, Kalienkova V, Lam AKM, Neldner Y, Dutzler R Nature. 2017 Dec 13. pii: nature24652. doi: 10.1038/nature24652. PMID:29236691<ref>PMID:29236691</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Lk3 transgenic mice]] |
| | [[Category: Dutzler, R]] | | [[Category: Dutzler, R]] |
| | [[Category: Kalienkova, V]] | | [[Category: Kalienkova, V]] |
| Structural highlights
Function
[ANO1_MOUSE] Calcium-activated chloride channel (CaCC) which plays an important role in transepithelial anion transport and smooth muscle contraction. Required for the normal functioning of the interstitial cells of Cajal (ICCs) which generate electrical pacemaker activity in gastrointestinal smooth muscles. Acts as a major contributor to basal and stimulated chloride conductance in airway epithelial cells and plays an important role in tracheal cartilage development.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The calcium-activated chloride channel TMEM16A is a ligand-gated anion channel that opens in response to an increase in intracellular Ca(2+) concentration. The protein is broadly expressed and contributes to diverse physiological processes, including transepithelial chloride transport and the control of electrical signalling in smooth muscles and certain neurons. As a member of the TMEM16 (or anoctamin) family of membrane proteins, TMEM16A is closely related to paralogues that function as scramblases, which facilitate the bidirectional movement of lipids across membranes. The unusual functional diversity of the TMEM16 family and the relationship between two seemingly incompatible transport mechanisms has been the focus of recent investigations. Previous breakthroughs were obtained from the X-ray structure of the lipid scramblase of the fungus Nectria haematococca (nhTMEM16), and from the cryo-electron microscopy structure of mouse TMEM16A at 6.6 A (ref. 14). Although the latter structure disclosed the architectural differences that distinguish ion channels from lipid scramblases, its low resolution did not permit a detailed molecular description of the protein or provide any insight into its activation by Ca(2+). Here we describe the structures of mouse TMEM16A at high resolution in the presence and absence of Ca(2+). These structures reveal the differences between ligand-bound and ligand-free states of a calcium-activated chloride channel, and when combined with functional experiments suggest a mechanism for gating. During activation, the binding of Ca(2+) to a site located within the transmembrane domain, in the vicinity of the pore, alters the electrostatic properties of the ion conduction path and triggers a conformational rearrangement of an alpha-helix that comes into physical contact with the bound ligand, and thereby directly couples ligand binding and pore opening. Our study describes a process that is unique among channel proteins, but one that is presumably general for both functional branches of the TMEM16 family.
Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM.,Paulino C, Kalienkova V, Lam AKM, Neldner Y, Dutzler R Nature. 2017 Dec 13. pii: nature24652. doi: 10.1038/nature24652. PMID:29236691[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Rock JR, Futtner CR, Harfe BD. The transmembrane protein TMEM16A is required for normal development of the murine trachea. Dev Biol. 2008 Sep 1;321(1):141-9. Epub 2008 Jun 14. PMID:18585372 doi:http://dx.doi.org/S0012-1606(08)00997-4
- ↑ Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008 Oct 30;455(7217):1210-5. Epub 2008 Aug 24. PMID:18724360 doi:http://dx.doi.org/nature07313
- ↑ Kunzelmann K, Schreiber R, Kmit A, Jantarajit W, Martins JR, Faria D, Kongsuphol P, Ousingsawat J, Tian Y. Expression and function of epithelial anoctamins. Exp Physiol. 2012 Feb;97(2):184-92. doi: 10.1113/expphysiol.2011.058206. Epub, 2011 Sep 9. PMID:21908539 doi:http://dx.doi.org/10.1113/expphysiol.2011.058206
- ↑ Sanders KM, Zhu MH, Britton F, Koh SD, Ward SM. Anoctamins and gastrointestinal smooth muscle excitability. Exp Physiol. 2012 Feb;97(2):200-6. doi: 10.1113/expphysiol.2011.058248. Epub 2011, Oct 14. PMID:22002868 doi:http://dx.doi.org/10.1113/expphysiol.2011.058248
- ↑ Duran C, Qu Z, Osunkoya AO, Cui Y, Hartzell HC. ANOs 3-7 in the anoctamin/Tmem16 Cl- channel family are intracellular proteins. Am J Physiol Cell Physiol. 2012 Feb 1;302(3):C482-93. doi:, 10.1152/ajpcell.00140.2011. Epub 2011 Nov 9. PMID:22075693 doi:http://dx.doi.org/10.1152/ajpcell.00140.2011
- ↑ Paulino C, Kalienkova V, Lam AKM, Neldner Y, Dutzler R. Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM. Nature. 2017 Dec 13. pii: nature24652. doi: 10.1038/nature24652. PMID:29236691 doi:http://dx.doi.org/10.1038/nature24652
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