1ttl
From Proteopedia
(New page: 200px<br /><applet load="1ttl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ttl" /> '''Omega-conotoxin GVIA, a N-type calcium chann...) |
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| - | [[Image:1ttl.gif|left|200px]]<br /><applet load="1ttl" size=" | + | [[Image:1ttl.gif|left|200px]]<br /><applet load="1ttl" size="350" color="white" frame="true" align="right" spinBox="true" |
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'''Omega-conotoxin GVIA, a N-type calcium channel blocker'''<br /> | '''Omega-conotoxin GVIA, a N-type calcium channel blocker'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The omega-conotoxins from fish-hunting cone snails are potent inhibitors | + | The omega-conotoxins from fish-hunting cone snails are potent inhibitors of voltage-gated calcium channels. The omega-conotoxins MVIIA and CVID are selective N-type calcium channel inhibitors with potential in the treatment of chronic pain. The beta and alpha(2)delta-1 auxiliary subunits influence the expression and characteristics of the alpha(1B) subunit of N-type channels and are differentially regulated in disease states, including pain. In this study, we examined the influence of these auxiliary subunits on the ability of the omega-conotoxins GVIA, MVIIA, CVID and analogues to inhibit peripheral and central forms of the rat N-type channels. Although the beta3 subunit had little influence on the on- and off-rates of omega-conotoxins, coexpression of alpha(2)delta with alpha(1B) significantly reduced on-rates and equilibrium inhibition at both the central and peripheral isoforms of the N-type channels. The alpha(2)delta also enhanced the selectivity of MVIIA, but not CVID, for the central isoform. Similar but less pronounced trends were also observed for N-type channels expressed in human embryonic kidney cells. The influence of alpha(2)delta was not affected by oocyte deglycosylation. The extent of recovery from the omega-conotoxin block was least for GVIA, intermediate for MVIIA, and almost complete for CVID. Application of a hyperpolarizing holding potential (-120 mV) did not significantly enhance the extent of CVID recovery. Interestingly, [R10K]MVIIA and [O10K]GVIA had greater recovery from the block, whereas [K10R]CVID had reduced recovery from the block, indicating that position 10 had an important influence on the extent of omega-conotoxin reversibility. Recovery from CVID block was reduced in the presence of alpha(2)delta in human embryonic kidney cells and in oocytes expressing alpha(1B-b). These results may have implications for the antinociceptive properties of omega-conotoxins, given that the alpha(2)delta subunit is up-regulated in certain pain states. |
==About this Structure== | ==About this Structure== | ||
| - | 1TTL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Conus_geographus Conus geographus] with NH2 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1TTL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Conus_geographus Conus geographus] with <scene name='pdbligand=NH2:'>NH2</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TTL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Conus geographus]] | [[Category: Conus geographus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Adams, D | + | [[Category: Adams, D J.]] |
| - | [[Category: Beedle, A | + | [[Category: Beedle, A M.]] |
| - | [[Category: Doering, C | + | [[Category: Doering, C J.]] |
| - | [[Category: Lewis, R | + | [[Category: Lewis, R J.]] |
[[Category: Mould, J.]] | [[Category: Mould, J.]] | ||
| - | [[Category: Schroeder, C | + | [[Category: Schroeder, C I.]] |
[[Category: Yasuda, T.]] | [[Category: Yasuda, T.]] | ||
| - | [[Category: Zamponi, G | + | [[Category: Zamponi, G W.]] |
[[Category: NH2]] | [[Category: NH2]] | ||
[[Category: amidated c-terminal]] | [[Category: amidated c-terminal]] | ||
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[[Category: four loop framework]] | [[Category: four loop framework]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:17:09 2008'' |
Revision as of 13:17, 21 February 2008
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Omega-conotoxin GVIA, a N-type calcium channel blocker
Overview
The omega-conotoxins from fish-hunting cone snails are potent inhibitors of voltage-gated calcium channels. The omega-conotoxins MVIIA and CVID are selective N-type calcium channel inhibitors with potential in the treatment of chronic pain. The beta and alpha(2)delta-1 auxiliary subunits influence the expression and characteristics of the alpha(1B) subunit of N-type channels and are differentially regulated in disease states, including pain. In this study, we examined the influence of these auxiliary subunits on the ability of the omega-conotoxins GVIA, MVIIA, CVID and analogues to inhibit peripheral and central forms of the rat N-type channels. Although the beta3 subunit had little influence on the on- and off-rates of omega-conotoxins, coexpression of alpha(2)delta with alpha(1B) significantly reduced on-rates and equilibrium inhibition at both the central and peripheral isoforms of the N-type channels. The alpha(2)delta also enhanced the selectivity of MVIIA, but not CVID, for the central isoform. Similar but less pronounced trends were also observed for N-type channels expressed in human embryonic kidney cells. The influence of alpha(2)delta was not affected by oocyte deglycosylation. The extent of recovery from the omega-conotoxin block was least for GVIA, intermediate for MVIIA, and almost complete for CVID. Application of a hyperpolarizing holding potential (-120 mV) did not significantly enhance the extent of CVID recovery. Interestingly, [R10K]MVIIA and [O10K]GVIA had greater recovery from the block, whereas [K10R]CVID had reduced recovery from the block, indicating that position 10 had an important influence on the extent of omega-conotoxin reversibility. Recovery from CVID block was reduced in the presence of alpha(2)delta in human embryonic kidney cells and in oocytes expressing alpha(1B-b). These results may have implications for the antinociceptive properties of omega-conotoxins, given that the alpha(2)delta subunit is up-regulated in certain pain states.
About this Structure
1TTL is a Single protein structure of sequence from Conus geographus with as ligand. Full crystallographic information is available from OCA.
Reference
The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels., Mould J, Yasuda T, Schroeder CI, Beedle AM, Doering CJ, Zamponi GW, Adams DJ, Lewis RJ, J Biol Chem. 2004 Aug 13;279(33):34705-14. Epub 2004 May 27. PMID:15166237
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