Peptide antagonists of ethanol inhibition of l1-mediated cell-cell adhesion.
Ethanol inhibits cell-cell adhesion mediated by the L1 cell adhesion molecule. 1-Octanol potently antagonizes this cellular action of ethanol and also prevents ethanol-induced dysmorphology and cell death in mouse whole embryo culture. NAPVSIPQ (NAP) and SALLRSIPA (SAL) are active peptide fragments of two neuroprotective proteins: activity-dependent neuroprotective protein and activity-dependent neurotrophic factor. NAP and SAL are neuroprotective at femtomolar concentrations against a variety of neurotoxins and also prevent ethanol teratogenesis in mice. To explore the cellular basis for this action, we asked whether NAP and SAL antagonize ethanol inhibition of L1 adhesion. Aggregation assays were carried out in ethanol-sensitive, human L1-transfected NIH/3T3 cells in the absence and presence of NAP and SAL. Neither NAP nor SAL altered L1 adhesion or L1 expression; however, both peptides potently and completely antagonized the inhibition of L1 adhesion by 100 mM ethanol (EC(50): NAP, 6 x 10(-14) M; SAL, 4 x 10(-11) M). NAP also antagonized ethanol inhibition of cell-cell adhesion in bone morphogenetic protein-7-treated NG108-15 cells. In L1-expressing NIH/3T3 cells, SAL antagonism was reversible and could be overcome by increasing concentrations of ethanol. In contrast, NAP antagonism was irreversible and could not be overcome by increasing agonist concentration. Two scrambled NAP peptides (ASPNQPIV and PNIQVASP) were not antagonists at concentrations as high as 10(-7) M. Thus, two structurally unrelated classes of compounds, alcohols and small polypeptides, share two common actions: antagonism of ethanol inhibition of L1-mediated cell adhesion and prevention of ethanol teratogenesis. These findings support the hypothesis that ethanol inhibition of L1 adhesion contributes to ethanol teratogenesis.
Wilkemeyer
Michael F
MF
Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Menkari
Carrie E
CE
Spong
Catherine Y
CY
Charness
Michael E
ME
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*
D009842:Oligopeptides; D000431:Ethanol