What can venom phospholipases A(2) tell us about the functional diversity of mammalian secreted phospholipases A(2)?

Most venomous animals including snakes, bees and scorpions contain a variet y of venom phospholipases A(2) (vPLA(2)s) which participate in both digesti on of prey and venom toxicity. So far, more than 150 vPLA(2)s have been cha racterized. They all have a conserved fold with several disulfide bridges, can be catalytically;active or not, and several of them can display a treme ndous array of toxic effects including neurotoxicity and myotoxicity. Furth ermore, the molecular diversity of vPLA(2)s found within a single snake ven om can result from positive Darwinian selection. Over the last decade, rece ptors and binding proteins for vPLA(2)s have been identified in mammals, su ggesting that vPLA(2)s can exert their toxicities through specific protein- protein interactions, besides their catalytic activity. The brain N-type re ceptors are involved in the neurotoxicity of vPLA(2)s, but are not yet clon ed. The M-type receptor has been cloned from skeletal muscle, belongs to th e superfamily of C-type lectins, and interestingly, has homology with vPLA( 2) inhibitors purified from snake blood. The molecular diversity of vPLA(2) s and the presence of receptors for vPLA(2)s in mammals raises the possibil ity that there is also a diversity of mammalian secreted PLA(2)s (msPLA(2)s ) which are the normal endogenous ligands of the vPLA(2) receptors. This vi ew led us to clone five novel msPLA(2)s (IID, IIE, IIF, III, and X msPLA(2) s), which together with the previously cloned msPLA(2)s (IB, IIA, IIC, and V), indicate that mammals also express a large diversity of sPLA(2)s. M-typ e receptors can have IB and IIA msPLA(2)s as natural endogenous ligands, su ggesting that ansPLA(2)s, like vPLA(2)s, can function as both enzymes and l igands. msPLA(2)s were first implicated in lipid digestion, and more recent ly in host defense mechanisms including inflammation and antibacterial defe nse. The growing molecular diversity of msPLA(2)s, which all have a specifi c tissue distribution, and the presence of receptors suggest that msPLA(2)s , like vPLA(2)s, are endowed with a wide array of biological effects which remain to be discovered. (C) 2000 Societe francais de biochimie et biologie moleculaire / Editions scientifiques et medicales Elsevier SAS.