title: 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.
authors: Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom.
authors: John-Paul
authors: JP
authors: Silva
authors: Vera G
authors: VG
authors: Lelianova
authors: Yaroslav S
authors: YS
authors: Ermolyuk
authors: Nickolai
authors: N
authors: Vysokov
authors: Paul G
authors: PG
authors: Hitchen
authors: Otto
authors: O
authors: Berninghausen
authors: M Atiqur
authors: MA
authors: Rahman
authors: Alice
authors: A
authors: Zangrandi
authors: Sara
authors: S
authors: Fidalgo
authors: Alexander G
authors: AG
authors: Tonevitsky
authors: Anne
authors: A
authors: Dell
authors: Kirill E
authors: KE
authors: Volynski
authors: Yuri A
authors: YA
authors: Ushkaryov
mesh_terms: D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling / Q000502:physiology*; D003001:Cloning, Molecular; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D015151:Immunoblotting; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C561456:Tenm2 protein, rat; C034800:alpha-latrotoxin receptor