| Structural highlights
Function
CA1A_CONRE This toxin target two types of receptors, the nicotinic acetylcholine receptor (nAChR) and the G-protein-coupled receptor GABA(B). It specifically inhibits the alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR, with preference for rat receptors (PubMed:16445293, PubMed:21888386, PubMed:22774872, PubMed:25740413, PubMed:28223528, PubMed:18242183, PubMed:18295795). It interacts with the alpha-10(+)/alpha-9(-)interface of the receptor (PubMed:25740413). It shows a two order of magnitude species difference potency for the rat versus human alpha-9-alpha-10 nAChR, due to the Thr-86 located in the alpha-9 nAChR subunit (PubMed:22774872). This toxin also shows inhibition of high voltage-activated (HVA) calcium channels (Cav2.2) by acting on GABA(B) receptors (GABBR1 and GABBR2) (PubMed:18945902, PubMed:21888386). In vivo, this toxin produces an acute antinociceptive effect in peripheral nerve-injured rats, which may be related to the inhibition of immune cell buildup at the site of nerve injury (PubMed:17101979). In addition, when intramuscularly injected into rats following chronic constriction injury of the sciatic nerve, this toxin protects peripheral nervous tissues as well as prevents central maladaptive plasticity by inhibiting glial cell activation (PubMed:25008370).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
alpha-Conotoxin RgIA is an antagonist of the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) subtype and also inhibits high voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with non-reducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets and stability evaluated in human serum. [3,12]-dicarba analogues retained inhibition of ACh-evoked currents at alpha9alpha10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8] dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.
Dicarba Analogues of alpha-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets.,Chhabra S, Belgi A, Bartels P, Vanlierop BJ, Robinson SD, Kompella SN, Hung A, Callaghan BP, Adams DJ, Robinson AJ, Norton RS J Med Chem. 2014 Nov 13. PMID:25393758[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ellison M, Haberlandt C, Gomez-Casati ME, Watkins M, Elgoyhen AB, McIntosh JM, Olivera BM. Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR. Biochemistry. 2006 Feb 7;45(5):1511-7. PMID:16445293 doi:http://dx.doi.org/10.1021/bi0520129
- ↑ Vincler M, Wittenauer S, Parker R, Ellison M, Olivera BM, McIntosh JM. Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17880-4. doi:, 10.1073/pnas.0608715103. Epub 2006 Nov 13. PMID:17101979 doi:http://dx.doi.org/10.1073/pnas.0608715103
- ↑ Clark RJ, Daly NL, Halai R, Nevin ST, Adams DJ, Craik DJ. The three-dimensional structure of the analgesic alpha-conotoxin, RgIA. FEBS Lett. 2008 Mar 5;582(5):597-602. doi: 10.1016/j.febslet.2008.01.027. Epub, 2008 Jan 31. PMID:18242183 doi:http://dx.doi.org/10.1016/j.febslet.2008.01.027
- ↑ Ellison M, Feng ZP, Park AJ, Zhang X, Olivera BM, McIntosh JM, Norton RS. Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J Mol Biol. 2008 Apr 4;377(4):1216-27. Epub 2008 Feb 4. PMID:18295795 doi:10.1016/j.jmb.2008.01.082
- ↑ Callaghan B, Haythornthwaite A, Berecki G, Clark RJ, Craik DJ, Adams DJ. Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J Neurosci. 2008 Oct 22;28(43):10943-51. doi: 10.1523/JNEUROSCI.3594-08.2008. PMID:18945902 doi:http://dx.doi.org/10.1523/JNEUROSCI.3594-08.2008
- ↑ Halai R, Callaghan B, Daly NL, Clark RJ, Adams DJ, Craik DJ. Effects of cyclization on stability, structure, and activity of alpha-conotoxin RgIA at the alpha9alpha10 nicotinic acetylcholine receptor and GABA(B) receptor. J Med Chem. 2011 Oct 13;54(19):6984-92. doi: 10.1021/jm201060r. Epub 2011 Sep 15. PMID:21888386 doi:http://dx.doi.org/10.1021/jm201060r
- ↑ Azam L, McIntosh JM. Molecular basis for the differential sensitivity of rat and human alpha9alpha10 nAChRs to alpha-conotoxin RgIA. J Neurochem. 2012 Sep;122(6):1137-44. doi: 10.1111/j.1471-4159.2012.07867.x. Epub, 2012 Aug 3. PMID:22774872 doi:http://dx.doi.org/10.1111/j.1471-4159.2012.07867.x
- ↑ Di Cesare Mannelli L, Cinci L, Micheli L, Zanardelli M, Pacini A, McIntosh JM, Ghelardini C. alpha-conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement. Pain. 2014 Oct;155(10):1986-95. doi: 10.1016/j.pain.2014.06.023. Epub 2014 Jul 5. PMID:25008370 doi:http://dx.doi.org/10.1016/j.pain.2014.06.023
- ↑ Azam L, Papakyriakou A, Zouridakis M, Giastas P, Tzartos SJ, McIntosh JM. Molecular interaction of alpha-conotoxin RgIA with the rat alpha9alpha10 nicotinic acetylcholine receptor. Mol Pharmacol. 2015 May;87(5):855-64. doi: 10.1124/mol.114.096511. Epub 2015 Mar , 4. PMID:25740413 doi:http://dx.doi.org/10.1124/mol.114.096511
- ↑ Romero HK, Christensen SB, Di Cesare Mannelli L, Gajewiak J, Ramachandra R, Elmslie KS, Vetter DE, Ghelardini C, Iadonato SP, Mercado JL, Olivera BM, McIntosh JM. Inhibition of alpha9alpha10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):E1825-E1832. doi:, 10.1073/pnas.1621433114. Epub 2017 Feb 21. PMID:28223528 doi:http://dx.doi.org/10.1073/pnas.1621433114
- ↑ Chhabra S, Belgi A, Bartels P, Vanlierop BJ, Robinson SD, Kompella SN, Hung A, Callaghan BP, Adams DJ, Robinson AJ, Norton RS. Dicarba Analogues of alpha-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets. J Med Chem. 2014 Nov 13. PMID:25393758 doi:http://dx.doi.org/10.1021/jm501126u
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