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.
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.
Køhler
Lene B
LB
Protein Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Panum Institute, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark.
Christensen
Claus
C
Rossetti
Clara
C
Fantin
Martina
M
Sandi
Carmen
C
Bock
Elisabeth
E
Berezin
Vladimir
V
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction
D019006:Neural Cell Adhesion Molecules; D010446:Peptide Fragments