Zhenyu Sheng, Zhong Liang, James H Geiger, Mary Prorok, Francis J Castellino
Index: Neuropharmacology 57(2) , 127-36, (2009)
Full Text: HTML
The conantokins are short, naturally occurring peptides that inhibit ion flow through N-methyl-d-aspartate receptor (NMDAR) channels. One member of this peptide family, conantokin-G (con-G), shows high selectivity for antagonism of NR2B-containing NMDAR channels, whereas other known conantokins are less selective inhibitors with regard to the nature of the NR2 subunit of the NMDAR complex. In order to define the molecular determinants of NR2B that govern con-G selectivity, we evaluated the ability of con-G to inhibit NMDAR ion channels expressed in human embryonic kidney (HEK)293 cells transfected with NR1, in combination with various NR2A/2B chimeras and point mutants, by electrophysiology using cells voltage-clamped in the whole-cell configuration. We found that a variant of the con-G-insensitive subunit, NR2A, in which the 158 residues comprising the S2 peptide segment (E(657)-I(814)) were replaced by the corresponding S2 region of NR2B (E(658)-I(815)), results in receptors that are highly sensitive to inhibition by con-G. Of the 22 amino acids that are different between the NR2A-S2 and the NR2B-S2 regions, exchange of one of these, M(739) of NR2B for the equivalent K(738) of NR2A, was sufficient to completely import the inhibitory activity of con-G into NR1b/NR2A-containing NMDARs. Some reinforcement of this effect was found by substitution of a second amino acid, K(755) of NR2B for Y(754) of NR2A. The discovery of the molecular determinants of NR2B selectivity with con-G has implications for the design of subunit-selective neurobiological probes and drug therapies, in addition to advancing our understanding of NR2B- versus NR2A-mediated neurological processes.
Structure | Name/CAS No. | Molecular Formula | Articles |
---|---|---|---|
![]() |
Conantokin G
CAS:93438-65-4 |
C88H138N26O44 |
NMDA/NR2B selective antagonists in the treatment of ischemic...
2005-04-01 [Curr. Drug Targets. CNS Neurol. Disord. 4(2) , 143-51, (2005)] |
The effect of CGX-1007 and CI-1041, novel NMDA receptor anta...
2004-03-01 [Epilepsy Res. 59(1) , 13-24, (2004)] |
Conantokins inhibit NMDAR-dependent calcium influx in develo...
2010-10-01 [Mol. Cell. Neurosci. 45(2) , 163-72, (2010)] |
Blockade of hindbrain NMDA receptors containing NR2 subunits...
2009-04-01 [Am. J. Physiol. Regul. Integr. Comp. Physiol. 296(4) , R921-8, (2009)] |
CGX-1007 prevents excitotoxic cell deathviaactions at multip...
2011-01-01 [Neurotoxicology 32 , 392-399, (2011)] |
Home | MSDS/SDS Database Search | Journals | Product Classification | Biologically Active Compounds | Selling Leads | About Us | Disclaimer
Copyright © 2024 ChemSrc All Rights Reserved