Prosaptide D5 reverses hyperalgesia: inhibition of calcium channels through a pertussis toxin-sensitive G-protein mechanism in the rat.
A retro-inverso 11-mer peptidomimetic of prosaposin, Prosaptide D5, induced neurite outgrowth in NS20Y neuroblastoma cells and enhanced [35S]GTPgammaS binding to rat synaptosomal membrane at low nanomolar concentrations similar to prosaposin. Intramuscular injection of D5 ameliorated thermal hyperalgesia in the Seltzer rat model of neuropathic pain, returning paw withdrawal latency to control levels within 3 h after treatment. The effect was sustained for at least 48 h after injection. Prosaposin and D5 inhibited K+-stimulated synaptosomal 45Ca2+ uptake similar to omega-conotoxin MVIIC, demonstrating that both effectors modulated voltage-dependent calcium channels (VDCC); inhibition was largely abolished by pretreatment with pertussis toxin before D5 treatment. The results suggest a mechanism whereby VDCC are modulated by a pertussis toxin-sensitive G-protein coupled receptor; D5 binds to this receptor and thereby ameliorates hyperalgesia in the Seltzer model of neuropathic pain.
Yan
L
L
Department of Neurosciences, School of Medicine, Center for Molecular Genetics, University of California, San Diego, La Jolla 92093-0634, USA.
Otero
D A
DA
Hiraiwa
M
M
O'Brien
J S
JS
D000818:Animals; D019771:Axotomy / Q000009:adverse effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects*; D017136:Ion Transport / Q000187:drug effects*; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D037342:Pertussis Toxin; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012584:Sciatic Nerve / Q000293:injuries; D013574:Synaptosomes / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015220:Calcium Channels; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010566:Virulence Factors, Bordetella; C404155:prosaptide D5; C404154:prosaptide D5y; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium