Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis

Abstract

In view of important neurobiological functions of the cell adhesion molecule contactin-6 (Cntn6) that have emerged from studies on null-mutant mice and autism spectrum disorders patients, we set out to examine pathways underlying functions of Cntn6 using a proteomics approach. We identified the cell adhesion GPCR latrophilin-1 (Lphn1, a.k.a. CIRL1/CL, ADGRL1) as a binding partner for Cntn6 forming together a heteromeric cis-complex. Lphn1 expression in cultured neurons caused reduction in neurite outgrowth and increase in apoptosis, which was rescued by coexpression of Cntn6. In cultured neurons derived from Cntn6-/- mice, Lphn1 knockdown reduced apoptosis, suggesting that the observed apoptosis was Lphn1-dependent. In line with these data, the number of apoptotic cells was increased in the cortex of Cntn6-/- mice compared to wild-type littermate controls. These results show that Cntn6 can modulate the activity of Lphn1 by direct binding and suggests that Cntn6 may prevent apoptosis thereby impinging on neurodevelopment.

Beyond the Ligand: Extracellular and Transcellular G Protein–Coupled Receptor Complexes in Physiology and Pharmacology

“…This protein belongs to the immunoglobulin superfamily and contains a large extracellular domain composed of six immunoglobulin-like domains and four FN3 domains tethered to the membrane by a GPI anchor. Contactin-6 has been demonstrated to form a cis-complex with ADGRL1 (Zuko et al, 2016). ADGRL1 expression in cultured neurons inhibits neurite outgrowth and increases apoptosis, whereas coexpression of contactin-6 reverses these processes (Zuko et al, 2016).…”

“…Contactin-6 has been demonstrated to form a cis-complex with ADGRL1 (Zuko et al, 2016). ADGRL1 expression in cultured neurons inhibits neurite outgrowth and increases apoptosis, whereas coexpression of contactin-6 reverses these processes (Zuko et al, 2016). Accordingly, cultured neurons from contactin-6 knockout mice show increased apoptosis, which is rescued by the knockdown of ADGRL1 (Zuko et al, 2016).…”

“…ADGRL1 expression in cultured neurons inhibits neurite outgrowth and increases apoptosis, whereas coexpression of contactin-6 reverses these processes (Zuko et al, 2016). Accordingly, cultured neurons from contactin-6 knockout mice show increased apoptosis, which is rescued by the knockdown of ADGRL1 (Zuko et al, 2016). Therefore, it appears the extracellular regulation of ADGRL1 via cis interactions with contactin-6 plays an important role in initiating or biasing signaling events necessary for maintaining neurite outgrowth and preventing apoptosis.…”

ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior

“…There have been increasing reports that some GPCRs engage in extracellular interactions with SAMs, both in cis and in trans; yet the role of this dimension in GPCR function is poorly understood. The primary example involves the ectodomain of adhesion GPCRs latrophilins (LPHNs), which directly interact with contactin-6 in cis, as well as teneurin-2/4, fibronectin leucine-rich transmembrane protein (FLRT) 2/3, and neurexin1-3 in trans [33][34][35][36][37][38] .…”

C‐terminal phosphorylation of latrophilin‐1/ADGRL1 affects the interaction between its fragments

“…In LPHN1, the two fragments have been shown to behave as partially independent proteins on the cell surface (see also below). All known ligands of LPHN1 (its natural agonist α‐LTX and its physiological partners: teneurin‐2, FLRT‐3, and contactin‐6) interact with its NTF. At least α‐LTX and teneurin‐2 induce NTF and CTF association and formation of large receptor complexes, generating intracellular signals .…”