GT1b Ganglioside Prevents Tetanus Toxin‐Induced Protein Kinase C Activation and Down‐Regulation in the Neonatal Brain In Vivo

Abstract

A single dose of 0.25 ng of tetanus toxin (TeTx), equivalent to -5 minimal lethal doses, injected intracerebrally to I -day-old rats, caused translocation, i.e., activation, of Ca'+-phosphatidylsenne-dependent protein kinase C (PKC) from the cytosolic to the membrane compartment within 1 h. Six hours after treatment with the toxin, a 40-50% reduction in the total brain PKC (cytosolic plus membrane) activity was noticed. G T l b (2 pg per brain) ganglioside, a putative receptor for TeTx, completely prevented enzyme translocation when injected intracerebrally 30 min before toxin administration and abolished down-regulation after 6 h from the time of toxin injection. GM1 (2 pg per brain), a ganglioside of lesser affinity for TeTx, produced by itself a 20-30% reduction of the total PKC activity and did not reverse TeTx-induced PKC down-regulation after 6 h. 12-O-Tetradecanoylphorbol

Tetanus Toxin Enhances Protein Kinase C Activity Translocation and Increases Polyphosphoinositide Hydrolysis in Rat Cerebral Cortex Preparations

“…This may be explained by the reversible nature of the interaction between the TeTx and specific binding sites on the cell plasma mcmbranc (Yavin Ct al., 1981). Whether gangliosides may serve as receptors for this interaction, as previously suggested (Aguilera et al, , 1993, remains to be studied. These data are analogous to other bacterial toxin-derived enzymatic activities (Shoshan et al, 1993) and growth factors such as interleukin-3, which stimulate a rapid and transient increase in the redistribution of PKC activity from the cytosol to the membrane (Farrar et al, 1985).…”

“…The latter mechanism is concurrent with our previous in vivo studies, showing activity translocation of Ca21iphosphatidylserine (Ca2~i PtdSer)-dependent protein kinase C (PKC) followed by down-regulation after intracerebral injection of TeTx in adult and immature rats . PKC translocation appeared before the classic symptoms of tetanus neurotoxicity in the perinatal rat (Aguilera et al, 1993). TeTx produces in vivo intoxication via a complex sequence of biochemical reactions, of which the Zn2t dependent metalloprotease activity probably represents the hallmark of its neurolethal action (Montecucco and Schiavo, 1994).…”

HC fragment (C-terminal portion of the heavy chain) of tetanus toxin activates protein kinase C isoforms and phosphoproteins involved in signal transduction

“…Later, our group described activation and subsequent down-regulation of PKC after intracerebral injection of TeTx into adult and neonatal rat brain [9]. PKC translocation appeared before the classic symptoms of tetanus neurotoxicity in the perinatal rat [10]. The increase in polyphosphoinositide hydrolysis in rat cerebral cortex preparations treated with TeTx indicates activation of phospholipases, an effect directly related to PKC activation [11].…”

Uptake and transport of clostridial neurotoxins

“…Signaling cascades are activated as a prelude to classical tetanus symptoms [195,196]. Gil et al further demonstrated activation of Trk receptors by H C T and TeNT, which trigger the activation of Akt and ERK1/2 in cultured cortical neurons [192].…”