Protein-tyrosine phosphatase-σ is a novel member of the functional family of α-latrotoxin receptors

Receptor-like protein-tyrosine phosphatase sigma (PTPsigma) is essential for neuronal development and function. Here we report that PTPsigma is a target of a-latrotoxin, a strong stimulator of neuronal exocytosis. a-Latrotoxin binds to the cell adhesion-like extracellular region of PTPsigma. This binding results in the stimulation of exocytosis. The toxin-binding site is located in the C-terminal part of the PTPsigma ectodomain and includes two fibronectin type III repeats. The intracellular catalytic domains of PTPsigma are not required for the alpha-latrotoxin binding and secretory response triggered by the toxin in chromaffin cells. These features of PTPsigma resemble two other previously described alpha-latrotoxin receptors, neurexin and CIRL. Thus, alpha-latrotoxin represents an unusual example of the neurotoxin that has three independent, equally potent, and yet structurally distinct targets. The known structural and functional characteristics of PTPsigma, neurexin, and CIRL suggest that they define a functional family of neuronal membrane receptors with complementary or converging roles in presynaptic function via a mechanism that involves cell-to-cell and cell-to-matrix interaction.