[A family of receptors for secretory phospholipases A2]

Venom phospholipases A2 (vPLA2's) display a large spectrum of toxic effects including neurotoxicity, myotoxicity, hypotensive, anticoagulant and proinflammatory effects. We have shown that these different types of effects are apparently linked to the existence of a diversity of very high affinity receptors (Kd values as low as 1.5 pM) for these toxic enzymes. On the other hand, mammalian secretory PLA2's (msPLA2's) are now implicated in many biological functions besides digestion, such as airway and vascular smooth muscle contraction, cell proliferation, and in a variety of diseases associated with inflammation such as rheumatoid arthritis, endotoxic shock, respiratory distress syndrome as well as in cancer diseases.... Several different types of receptors (N and M) have been identified for vPLA2's and one of them (180 kDa, called M) has been cloned in rabbit and man. It is a membrane protein with a N-terminal cystein-rich domain, a fibronectin-like type II domain, eight repeats of a carbohydrate recognition domain, a unique transmembrane and an intracellular C-terminal. When expressed in transfected cells, the rabbit M-type receptor binds both the inflammatory-type and the pancreatic-type msPLA2's with fairly high affinities (Kd approximately -1-10 nM) suggesting that the sPLA2 receptors we have identifying vPLA2's are the normal targets of endogenous msPLA2's involved in a variety of diseases. Residues within or close to the Ca2+ binding loop of pancreatic-type PLA2 are crucially involved in the binding step although the presence of Ca2+ which is essential for the enzymatic activity is not required for binding to the receptor. The domain in charge of sPLA2 binding in the M-type receptor has been identified. The M-type receptor is an endocytic receptor that rapidly internalizes its sPLA2 ligand.