A dimeric version of the short N-cadherin binding motif HAVDI promotes neuronal cell survival by activating an N-cadherin/fibroblast growth factor receptor signalling cascade.
The HAVDI and INPISGQ sequences have been identified as functional binding motifs in extracellular domain 1 (ECD1) of N-cadherin. Cyclic peptides containing a tandem repeat of the individual motifs function as N-cadherin agonists and stimulate neurite outgrowth. We now show that the cyclic peptide N-Ac-CHAVDINGHAVDIC-NH2 (SW4) containing the HAVDI sequence in tandem is efficacious also in promoting the in vitro survival of several populations of central nervous system neurons in paradigms where fibroblast growth factor-2 (FGF-2) is active. SW4 supported the survival of rat postnatal cerebellar granule neurons plated in serum-free medium and limited the death of differentiated granule neurons induced to die by switch to low K+ medium. In addition, SW4 rescued embryonic hippocampal and cortical neurons from injury caused by glutamic acid excitotoxicity. The neuroprotective effects of SW4 displayed a concentration dependence similar to those inducing neuritogenesis, were inhibited by a monomeric version of the same motif and by a specific FGF receptor antagonist (PD173074), and were not mimicked by the linear peptide. Inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase), MAP kinase, and p38 kinase signalling pathways did not interfere with SW4 function. These data suggest that SW4 functions by binding to and clustering N-cadherin in neurons and thereby activating and N-cadherin/FGF receptor signalling cascade, and propose that such agonists may represent a starting point for the development of therapeutic agents promoting neuronal cell survival and regeneration.
Skaper
Stephen D
SD
Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Harlow CM19 5AW, Essex, UK. Stephen_Skaper-1@gsk.com
Facci
Laura
L
Williams
Gareth
G
Williams
Emma-Jane
EJ
Walsh
Frank S
FS
Doherty
Patrick
P
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000502:physiology; D015820:Cadherins / Q000737:chemistry* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D015820:Cadherins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2