Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models
Abstractα-Conotoxins from Conus snails are capable of distinguishing muscle and neuronal nicotinic acetylcholine receptors (nAChRs). α-Conotoxin RgIA and αO-conotoxin GeXIVA, blocking neuronal α9α10 nAChR, are potential analgesics. Typically, α-conotoxins bind to the orthosteric sites for agonists/competitive antagonists, but αO-conotoxin GeXIVA was proposed to attach allosterically, judging by electrophysiological experiments on α9α10 nAChR. We decided to verify this conclusion by radioligand analysis in competition with α-bungarotoxin (αBgt) on the ligand-binding domain of the nAChR α9 subunit (α9 LBD), where, from the X-ray analysis, αBgt binds at the orthosteric site. A competition with αBgt was registered for GeXIVA and RgIA, IC50 values being in the micromolar range. However, high nonspecific binding of conotoxins (detected with their radioiodinated derivatives) to His6-resin attaching α9 LBD did not allow us to accurately measure IC50s. However, IC50s were measured for binding to Aplysia californica AChBP: the RgIA globular isomer, known to be active against α9α10 nAChR, was more efficient than the ribbon one, whereas all three GeXIVA isomers had similar potencies at low µM. Thus, radioligand analysis indicated that both conotoxins can attach to the orthosteric sites in these nAChR models, which should be taken into account in the design of analgesics on the basis of these conotoxins. View Full-Text
Share & Cite This Article
Kryukova, E.V.; Ivanov, I.A.; Lebedev, D.S.; Spirova, E.N.; Egorova, N.S.; Zouridakis, M.; Kasheverov, I.E.; Tzartos, S.J.; Tsetlin, V.I. Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models. Mar. Drugs 2018, 16, 460.
Kryukova EV, Ivanov IA, Lebedev DS, Spirova EN, Egorova NS, Zouridakis M, Kasheverov IE, Tzartos SJ, Tsetlin VI. Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models. Marine Drugs. 2018; 16(12):460.Chicago/Turabian Style
Kryukova, Elena V.; Ivanov, Igor A.; Lebedev, Dmitry S.; Spirova, Ekaterina N.; Egorova, Natalia S.; Zouridakis, Marios; Kasheverov, Igor E.; Tzartos, Socrates J.; Tsetlin, Victor I. 2018. "Orthosteric and/or Allosteric Binding of α-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models." Mar. Drugs 16, no. 12: 460.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.