Dennexin peptides modeled after the homophilic binding sites of the neural cell adhesion molecule (NCAM) promote neuronal survival, modify cell adhesion and impair spatial learning

TY - JOUR

T1 - Dennexin peptides modeled after the homophilic binding sites of the neural cell adhesion molecule (NCAM) promote neuronal survival, modify cell adhesion and impair spatial learning

AU - Køhler, Lene B

AU - Christensen, Claus

AU - Rossetti, Clara

AU - Fantin, Martina

AU - Sandi, Carmen

AU - Bock, Elisabeth

AU - Berezin, Vladimir

N1 - Copyright 2010 Elsevier GmbH. All rights reserved.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Neural cell adhesion molecule (NCAM)-mediated cell adhesion results in activation of intracellular signaling cascades that lead to cellular responses such as neurite outgrowth, neuronal survival, and modulation of synaptic activity associated with cognitive processes. The crystal structure of the immunoglobulin (Ig) 1-2-3 fragment of the NCAM ectodomain has revealed novel mechanisms for NCAM homophilic adhesion. The present study addressed the biological significance of the so called dense zipper formation of NCAM. Two peptides, termed dennexinA and dennexinB, were modeled after the contact interfaces between Ig1 and Ig3 and between Ig2 and Ig2, respectively, observed in the crystal structure. Although the two dennexin peptides differed in amino acid sequence, they both modulated cell adhesion, reflected by inhibition of NCAM-mediated neurite outgrowth. Both dennexins also promoted neuronal survival, and the effect of dennexinA was independent of polysialic acid expression. Consistent with the effect of dennexinA on NCAM-mediated adhesion in vitro, the peptide impaired long-term memory retention in rats in the Morris water maze test. Thus, dennexins are novel site-specific pharmacological tools for elucidation of the role of NCAM in a variety of biological processes under normal and pathological conditions.

AB - Neural cell adhesion molecule (NCAM)-mediated cell adhesion results in activation of intracellular signaling cascades that lead to cellular responses such as neurite outgrowth, neuronal survival, and modulation of synaptic activity associated with cognitive processes. The crystal structure of the immunoglobulin (Ig) 1-2-3 fragment of the NCAM ectodomain has revealed novel mechanisms for NCAM homophilic adhesion. The present study addressed the biological significance of the so called dense zipper formation of NCAM. Two peptides, termed dennexinA and dennexinB, were modeled after the contact interfaces between Ig1 and Ig3 and between Ig2 and Ig2, respectively, observed in the crystal structure. Although the two dennexin peptides differed in amino acid sequence, they both modulated cell adhesion, reflected by inhibition of NCAM-mediated neurite outgrowth. Both dennexins also promoted neuronal survival, and the effect of dennexinA was independent of polysialic acid expression. Consistent with the effect of dennexinA on NCAM-mediated adhesion in vitro, the peptide impaired long-term memory retention in rats in the Morris water maze test. Thus, dennexins are novel site-specific pharmacological tools for elucidation of the role of NCAM in a variety of biological processes under normal and pathological conditions.

KW - Amino Acid Sequence

KW - Animals

KW - Binding Sites

KW - Cell Adhesion

KW - Cell Line

KW - Male

KW - Maze Learning

KW - Mice

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Neural Cell Adhesion Molecules

KW - Neurites

KW - Neurons

KW - Peptide Fragments

KW - Rats

KW - Rats, Sprague-Dawley

KW - Rats, Wistar

KW - Signal Transduction

U2 - 10.1016/j.ejcb.2010.07.007

DO - 10.1016/j.ejcb.2010.07.007

M3 - Journal article

C2 - 20692716

SN - 0724-5130

VL - 89

SP - 817

EP - 827

JO - Cytobiologie

JF - Cytobiologie

IS - 11

ER -