PMID- 24260577
OWN - NLM
STAT- MEDLINE
DCOM- 20140630
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 11
DP  - 2013
TI  - Antagonist properties of Conus parius peptides on N-methyl-D-aspartate receptors 
      and their effects on CREB signaling.
PG  - e81405
LID - 10.1371/journal.pone.0081405 [doi]
LID - e81405
AB  - Three members of a family of small neurotoxic peptides from the venom of Conus 
      parius, conantokins (Con) Pr1, Pr2, and Pr3, function as antagonists of 
      N-methyl-D-aspartate receptors (NMDAR). We report structural characterizations of 
      these synthetic peptides, and also demonstrate their antagonistic properties 
      toward ion flow through NMDAR ion channels in primary neurons. ConPr1 and ConPr2 
      displayed moderate increases in alpha-helicity after addition of Mg(2+). Native 
      apo-ConPr3 possessed an alpha-helical conformation, and the helicity increased only 
      slightly on addition of Mg(2+). Additionally, these peptides diminished 
      NMDA/Gly-mediated currents and intracellular Ca(2+) (iCa(2+)) influx in mature 
      rat primary hippocampal neurons. Electrophysiological data showed that these 
      peptides displayed slower antagonistic properties toward the NMDAR than 
      conantokins from other species of cone snails, e.g., ConT and ConG. Furthermore, 
      to demonstrate selectivity of the C. parius-derived conantokins towards specific 
      NMDAR subunits, cortical neurons from GluN2A(-/-) and GluN2B(-/-) mice were 
      utilized. Robust inhibition of NMDAR-mediated stimulation in GluN2A(-/-)-derived 
      mouse neurons, as compared to those isolated from GluN2B(-/-)-mouse brains, was 
      observed, suggesting a greater selectivity of these antagonists towards the 
      GluN2B subunit. These C. parius conantokins mildly inhibited NMDAR-induced 
      phosphorylation of CREB at Ser(133), suggesting that the peptides modulated 
      iCa(2+) entry and, thereby, activation of CREB, a transcription factor that is 
      required for maintaining long-term synaptic activity. Our data mechanistically 
      show that while these peptides effectively antagonize NMDAR-directed current and 
      iCa(2+) influx, receptor-coupled CREB signaling is maintained. The consequence of 
      sustained CREB signaling is improved neuronal plasticity and survival during 
      neuropathologies.
FAU - Kunda, Shailaja
AU  - Kunda S
AD  - W.M. Keck Center for Transgene Research and Department of Chemistry and 
      Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of 
      America.
FAU - Cheriyan, John
AU  - Cheriyan J
FAU - Hur, Michael
AU  - Hur M
FAU - Balsara, Rashna D
AU  - Balsara RD
FAU - Castellino, Francis 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 - 20131118
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Conotoxins)
RN  - 0 (Mollusk Venoms)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.3.1.48 (CREB-Binding Protein)
RN  - EC 2.3.1.48 (Crebbp protein, mouse)
RN  - I38ZP9992A (Magnesium)
RN  - SY7Q814VUP (Calcium)
RN  - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A)
SB  - IM
MH  - Animals
MH  - CREB-Binding Protein/genetics/*metabolism
MH  - Calcium/metabolism
MH  - Conotoxins/chemical synthesis/chemistry/*pharmacology
MH  - Conus Snail/physiology
MH  - Gene Expression Regulation
MH  - Hippocampus/cytology/drug effects/metabolism
MH  - Magnesium/chemistry
MH  - Male
MH  - Mice
MH  - Mollusk Venoms/*chemistry
MH  - Neuronal Plasticity
MH  - Neurons/cytology/*drug effects/metabolism
MH  - Phosphorylation
MH  - Primary Cell Culture
MH  - Protein Structure, Secondary
MH  - Protein Subunits/antagonists & inhibitors/genetics/metabolism
MH  - Rats
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & 
      inhibitors/deficiency/genetics/metabolism
MH  - Signal Transduction/*drug effects
PMC - PMC3832412
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/11/22 06:00
MHDA- 2014/07/01 06:00
PMCR- 2013/11/18
CRDT- 2013/11/22 06:00
PHST- 2013/08/14 00:00 [received]
PHST- 2013/10/22 00:00 [accepted]
PHST- 2013/11/22 06:00 [entrez]
PHST- 2013/11/22 06:00 [pubmed]
PHST- 2014/07/01 06:00 [medline]
PHST- 2013/11/18 00:00 [pmc-release]
AID - PONE-D-13-33347 [pii]
AID - 10.1371/journal.pone.0081405 [doi]
PST - epublish
SO  - PLoS One. 2013 Nov 18;8(11):e81405. doi: 10.1371/journal.pone.0081405. 
      eCollection 2013.