Latrophilin‐1 is an adhesion G protein–coupled receptor that mediates the effect of α‐latrotoxin, causing massive release of neurotransmitters from nerve terminals and endocrine cells. Autoproteolysis cleaves latrophilin‐1 into two parts: the extracellular N‐terminal fragment (NTF) and the heptahelical C‐terminal fragment (CTF). NTF and CTF can exist as independent proteins in the plasma membrane, but α‐latrotoxin binding to NTF induces their association and G protein–mediated signaling. We demonstrate here that CTF in synapses is phosphorylated on multiple sites. Phosphorylated CTF has a high affinity for NTF and copurifies with it on affinity columns and sucrose density gradients. Dephosphorylated CTF has a lower affinity for NTF and can behave as a separate protein. α‐Latrotoxin (and possibly other ligands of latrophilin‐1) binds both to the NTF–CTF complex and receptor‐like protein tyrosine phosphatase σ, bringing them together. This leads to CTF dephosphorylation and facilitates CTF release from the complex. We propose that ligand‐dependent phosphorylation‐dephosphorylation of latrophilin‐1 could affect the interaction between its fragments and functions as a G protein–coupled receptor.