A novel neurotrophic role of secretory phospholipases A₂ for cerebellar granule neurons

Abstract

Cultured cerebellar granule neurons (CGNs) require membrane depolarization or neurotrophic factors for their survival in vitro and undergo apoptosis when deprived of these survival-promoting stimuli. Here, we show that secretory phospholipases A 2 s (sPLA 2 s) rescue CGNs from apoptosis after potassium deprivation. The neurotrophic effect required the enzymatic activity of sPLA 2 s, since catalytically inactive mutants of sPLA 2 s failed to protect CGNs from apoptosis. Consistently, the ability of sPLA 2 s to protect CGNs from apoptosis correlated with the extent of sPLA 2 -induced arachidonic acid release from live CGNs. The survival-promoting effect of sPLA 2 was inhibited by depletion of extracellular Ca 2+ or by the presence of L-type Ca 2+ channel blocker nicardipine, suggesting that Ca 2+ influx occurs upon sPLA 2 treatment. Among the mammalian sPLA 2 s tested, only group X sPLA 2 , but not group IB nor IIA sPLA 2 s, displayed neurotrophic activity. These results suggest a novel, unexpected neurotrophin-like role of sPLA 2 in the nervous system.

Upregulation of Fas and FasL in Taiwan cobra phospholipase A2‐treated human neuroblastoma SK‐N‐SH cells through ROS‐ and Ca2+‐mediated p38 MAPK activation

“…It was evident that the action of PLA 2 and BPB-PLA 2 is mediated by ROS generated from NADPH oxidase. channel Yagami et al, 2003a,b;Arioka et al, 2005]. As illustrated in Figure 7A,B, it showed that [Ca 2þ ]i was notably increased after treatment with PLA 2 and BPB-PLA 2 for 30 min and then declined to the level indistinguishable from that of untreated control cells.…”

Expression profile of multiple secretory phospholipase A2 isoforms in the rat CNS: Enriched expression of sPLA2-IIA in brainstem and spinal cord

“…This, postulated role of sPLA 2 -IIA as a secreted neuromodulator during synaptic transmission seems consistent with previous findings that sPLA 2 plays role in membrane depolarization and Ca 2+ entry, necessary for maintenance of healthy neurons: cerebellar granule neurons require membrane depolarization and neurotrophic factors to survive in vitro, and sPLA 2 was shown to protect these neurons from apoptosis caused by K + deprivation. Moreover, the ability of sPLA 2 to promote neuronal survival is inhibited when extracellular Ca 2+ is depleted or when Ltype Ca 2+ channel is blocked by nicardipine (Arioka et al, 2005).…”

Group X secreted phospholipase A2 induces lipid droplet formation and prolongs breast cancer cell survival

“…Several mammalian sPLA 2 s have been shown to stimulate cell proliferation in cancer cells [18,19,22,25]. An anti-apoptotic role in growth factor-deprived cells has been shown for the group IIA in kidney fibroblasts [65], and for the group III and X sPLA 2 s in neuronal cultures [66,67]. The enzymatic activity-dependent mechanisms reported [18,22,65] have usually been associated with the pleiotropic actions of AA-derived eicosanoids [25] and rarely with lysophospholipids [26,66].…”