Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities

Abstract

Latrophilin 1 (LPH1), a neuronal receptor of α-latrotoxin, is implicated in neurotransmitter release and control of presynaptic Ca 2+ . As an "adhesion G-protein-coupled receptor," LPH1 can convert cell surface interactions into intracellular signaling. To examine the physiological functions of LPH1, we used LPH1's extracellular domain to purify its endogenous ligand. A single protein of ∼275 kDa was isolated from rat brain and termed Lasso. Peptide sequencing and molecular cloning have shown that Lasso is a splice variant of teneurin-2, a brain-specific orphan cell surface receptor with a function in neuronal pathfinding and synaptogenesis. We show that LPH1 and Lasso interact strongly and specifically. They are always copurified from rat brain extracts. Coculturing cells expressing LPH1 with cells expressing Lasso leads to their mutual attraction and formation of multiple junctions to which both proteins are recruited. Cells expressing LPH1 form chimerical synapses with hippocampal neurons in cocultures; LPH1 and postsynaptic neuronal protein PSD-95 accumulate on opposite sides of these structures. Immunoblotting and immunoelectron microscopy of purified synapses and immunostaining of cultured hippocampal neurons show that LPH1 and Lasso are enriched in synapses; in both systems, LPH1 is presynaptic, whereas Lasso is postsynaptic. A C-terminal fragment of Lasso interacts with LPH1 and induces Ca 2+ signals in presynaptic boutons of hippocampal neurons and in neuroblastoma cells expressing LPH1. Thus, LPH1 and Lasso can form transsynaptic complexes capable of inducing presynaptic Ca 2+ signals, which might affect synaptic functions.

In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation

“…Teneurins are required for transsynaptic signaling and organization of the synapse cytoskeleton in Drosophila neuromuscular synapses and olfactory receptor neurons (33,86). Recently, mammalian teneurins have been shown to be latrophilin (Lphn) receptors, which are known to mediate the massive synaptic exocytosis caused by the black widow spider venom α-latrotoxin and which also were identified as reduced in deprived synapses (48,87). Prickle2 has been shown to regulate neurite formation and outgrowth, but only in neuroblastoma cell lines (55).…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…A further feature of the Adhesion GPCR binding profile seems to be a high promiscuity in ligand recognition, with one receptor binding to multiple partners. Lastly, the location of these partners is not always found on opposing cells or in the extracellular space (in trans: Hamann et al, 1996b;Park et al, 2007;Das et al, 2011;Silva et al, 2011); in some cases, receptor and ligand may reside on the surface of the same cell (in cis: Little et al, 2004;Nishimura et al, 2012;Prömel et al, 2012a).…”

“…ADGRLs (latrophilins) are well studied with regard to interacting partner binding, and recently, teneurin-2 (also known as Lasso) was suggested to be an endogenous binding partner for ADGRL1 (latrophilin-1) (Silva et al, 2011). In rats, teneurin-2 interacts strongly and specifically with ADGRL1 (latrophilin-1) in trans (Silva et al, 2011) (Fig.…”

The role of G protein-coupled receptors in the early evolution of neurotransmission and the nervous system

“…2), subfamily I latrophilins are well known for their roles in synapse development and triggering neurotransmitter release. The presynaptic latrophilin 1 (LPHN1) interacts with the postsynaptic teneurin-2 (also known as Lasso, an endogenous ligand of latrophilin 1), forming a trans-synaptic complex and thus affecting synaptic development (Boucard et al, 2014;Silva et al, 2011). And, latrophilins interact with the postsynaptic fibronectin leucine-rich transmembrane (FLRT) family members.…”