PMID- 20688135
OWN - NLM
STAT- MEDLINE
DCOM- 20110111
LR  - 20211020
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 170
IP  - 3
DP  - 2010 Oct 27
TI  - Specific determinants of conantokins that dictate their selectivity for the NR2B 
      subunit of N-methyl-D-aspartate receptors.
PG  - 703-10
LID - 10.1016/j.neuroscience.2010.07.056 [doi]
AB  - Conantokins are naturally-occurring small peptide antagonists of ion flow through 
      NMDA/glycine activated-N-methyl-d-aspartate receptor (NMDAR) ion channels. One 
      member of the conantokin family, conantokin (con)-G, a 17-residue peptide, is 
      selective for NMDARs containing the N-methyl-d-aspartate receptor subunit 2 B 
      (NR2B), whereas the homologous peptides, con-T and con-R, show broader 
      selectivity for NR2 subunits. In this study, con-G, con-R, and con-T variants 
      were chemically synthesized and employed to investigate their subunit 
      selectivities as inhibitors of agonist-evoked ion currents in human embryonic 
      kidney-293 (HEK-293) cells expressing various combinations of NMDAR subunits that 
      contain NR1a or NR1b combined with NR2A or NR2B. Using truncation and point 
      mutants, as well as chimeric conantokins, we determined that the N-terminus of 
      con-G contains all the determinants for NR2B selectivity. With this information, 
      a large number of (con) variants were synthesized and used to establish minimal 
      sequence determinants for selectivity. Tyr at position 5 broadens the NR2 
      selectivity, and recovery of NR2B selectivity in Tyr5 peptides was achieved by 
      incorporating Ala or Gly at position 8. NR2B selectivity in con-R can be 
      conferred through deletion of the Ala at position 10, thereby shifting the 
      gamma-carboxyglutamate (Gla) from position 11 to position 10, where a Gla naturally 
      occurs in con-G and con-T. The nature of the amino acid at position 6 is also 
      linked to subunit selectivity. Our studies suggest that the molecular 
      determinants of conantokins that dictate NMDAR subunit selectivity are housed in 
      specific residues of the N-termini of these peptides. Thus, it is possible to 
      engineer desired NMDAR functional properties into conantokin-based peptides.
CI  - Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Sheng, Z
AU  - Sheng Z
AD  - W. M. Keck Center for Transgene Research and Department of Chemistry and 
      Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
FAU - Prorok, M
AU  - Prorok M
FAU - Castellino, F J
AU  - Castellino FJ
LA  - eng
GR  - R01 HL019982/HL/NHLBI NIH HHS/United States
GR  - HL019982/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100803
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Conotoxins)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Mollusk Venoms)
RN  - 0 (Peptides)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (conantokin R)
RN  - 127476-26-0 (conantokin-T)
RN  - 93438-65-4 (conotoxin GV)
SB  - IM
MH  - Amino Acid Sequence
MH  - Conotoxins/chemical synthesis/chemistry/*pharmacology
MH  - Excitatory Amino Acid Antagonists/chemical synthesis/chemistry/*pharmacology
MH  - HEK293 Cells
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins
MH  - Mollusk Venoms/chemical synthesis/chemistry/*pharmacology
MH  - Patch-Clamp Techniques
MH  - Peptides/chemical synthesis/chemistry/*pharmacology
MH  - Point Mutation
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/genetics
MH  - Transfection/methods
PMC - PMC2939254
MID - NIHMS227394
EDAT- 2010/08/07 06:00
MHDA- 2011/01/12 06:00
PMCR- 2011/10/27
CRDT- 2010/08/07 06:00
PHST- 2010/07/06 00:00 [received]
PHST- 2010/07/26 00:00 [revised]
PHST- 2010/07/28 00:00 [accepted]
PHST- 2010/08/07 06:00 [entrez]
PHST- 2010/08/07 06:00 [pubmed]
PHST- 2011/01/12 06:00 [medline]
PHST- 2011/10/27 00:00 [pmc-release]
AID - S0306-4522(10)01059-6 [pii]
AID - 10.1016/j.neuroscience.2010.07.056 [doi]
PST - ppublish
SO  - Neuroscience. 2010 Oct 27;170(3):703-10. doi: 10.1016/j.neuroscience.2010.07.056. 
      Epub 2010 Aug 3.