Signaling by latrophilin adhesion-GPCRs in synapse assembly

Latrophilins are evolutionarily conserved adhesion-GPCRs with diverse roles, including a prominent function in synapse organization. In mammals, the primary transcripts of three latrophilin genes (ADGRL1-3) are extensively alternatively spliced, producing hundreds of isoforms with diverse cytoplasmic sequences. Extracellularly, latrophilins feature N-terminal lectin- and olfactomedin-like domains that bind to Teneurin and FLRT adhesion molecules, respectively, and are followed by an autoproteolytic GAIN domain typical for adhesion-GPCRs. Since Teneurins and FLRTs in turn interact with other ligands, latrophilins form a large trans-cellular protein interaction network. Intracellularly, latrophilins bind to G proteins, arrestins, and postsynaptic scaffold proteins. Latrophilins stimulate all Gα proteins tested, with the Gα isoform preference regulated by alternative splicing. In brain, latrophilins act as essential postsynaptic organizers that functionally require extracellular binding to teneurins and FLRTs, intracellular activation of GαS, and recruitment of postsynaptic scaffolds. Thus, latrophilins are signaling platforms that connect trans-cellular interactions to cellular responses in a manner regulated by alternative splicing.