Latrophilin GPCR signaling mediates synapse formation

Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.

[1]  E. Gray.  Neurological Diseases , 1969, Nature.

[2]  G. Tall,et al.  Mechanisms of adhesion G protein–coupled receptor activation , 2020, The Journal of Biological Chemistry.

[3]  T. Südhof,et al.  A Synaptic Circuit Required for Acquisition but Not Recall of Social Transmission of Food Preference , 2020, Neuron.

[4]  T. Südhof,et al.  Latrophilin-2 and latrophilin-3 are redundantly essential for parallel-fiber synapse function in cerebellum , 2020, eLife.

[5]  Erwin G. Van Meir,et al.  The expanding functional roles and signaling mechanisms of adhesion G protein–coupled receptors , 2019, Annals of the New York Academy of Sciences.

[6]  J. Arias-Montaño,et al.  Alternative splicing event modifying ADGRL1/latrophilin‐1 cytoplasmic tail promotes both opposing and dual cAMP signaling pathways , 2019, Annals of the New York Academy of Sciences.

[7]  A. Ribic,et al.  Emerging Roles of Synapse Organizers in the Regulation of Critical Periods , 2019, Neural plasticity.

[8]  Stefanie Giera,et al.  Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases. , 2019, Trends in pharmacological sciences.

[9]  T. Südhof,et al.  Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins , 2019, Science.

[10]  D. Araç,et al.  Teneurins and latrophilins: two giants meet at the synapse. , 2019, Current opinion in structural biology.

[11]  T. Südhof,et al.  Cbln2 and Cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs , 2018, Proceedings of the National Academy of Sciences.

[12]  T. Südhof,et al.  Towards an Understanding of Synapse Formation , 2018, Neuron.

[13]  J. Hell,et al.  Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca2+/CaMKII signaling , 2018, The EMBO journal.

[14]  J. Sanes,et al.  Cadherin Combinations Recruit Dendrites of Distinct Retinal Neurons to a Shared Interneuronal Scaffold , 2018, Neuron.

[15]  Z. Nusser.  Creating diverse synapses from the same molecules , 2018, Current Opinion in Neurobiology.

[16]  T. Südhof,et al.  Genetic Ablation of All Cerebellins Reveals Synapse Organizer Functions in Multiple Regions Throughout the Brain , 2018, The Journal of Neuroscience.

[17]  G. Tall,et al.  A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1 , 2018, iScience.

[18]  Eunjoon Kim,et al.  SALM/Lrfn Family Synaptic Adhesion Molecules , 2018, Front. Mol. Neurosci..

[19]  John D. Scott,et al.  Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors , 2018, The Journal of Neuroscience.

[20]  M. Yuzaki.  Two Classes of Secreted Synaptic Organizers in the Central Nervous System. , 2018, Annual review of physiology.

[21]  R. Purcell,et al.  Adhesion G Protein-Coupled Receptors as Drug Targets. , 2018, Annual review of pharmacology and toxicology.

[22]  T. Südhof,et al.  Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly , 2017, The Journal of cell biology.

[23]  O. Torres-Quesada,et al.  The many faces of compartmentalized PKA signalosomes. , 2017, Cellular signalling.

[24]  H. Hirase,et al.  Red fluorescent protein-based cAMP indicator applicable to optogenetics and in vivo imaging , 2017, Scientific Reports.

[25]  G. Nagel,et al.  Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons , 2017, eLife.

[26]  M. Halls,et al.  Compartmentalization of GPCR signalling controls unique cellular responses. , 2016, Biochemical Society Transactions.

[27]  R. Purcell,et al.  Stalk-dependent and Stalk-independent Signaling by the Adhesion G Protein-coupled Receptors GPR56 (ADGRG1) and BAI1 (ADGRB1)* , 2015, The Journal of Biological Chemistry.

[28]  Anirvan Ghosh,et al.  Specification of synaptic connectivity by cell surface interactions , 2015, Nature Reviews Neuroscience.

[29]  R. Schnabel,et al.  Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1 , 2015, PLoS genetics.

[30]  Philippe Isope,et al.  The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells. , 2015, Cell reports.

[31]  Soichi Nagao,et al.  Anterograde C1ql1 Signaling Is Required in Order to Determine and Maintain a Single-Winner Climbing Fiber in the Mouse Cerebellum , 2015, Neuron.

[32]  James P. White,et al.  New functions and signaling mechanisms for the class of adhesion G protein–coupled receptors , 2014, Annals of the New York Academy of Sciences.

[33]  W. Weis,et al.  Modified T4 Lysozyme Fusion Proteins Facilitate G Protein-Coupled Receptor Crystallogenesis. , 2014, Structure.

[34]  Satoshi Arai,et al.  Genetically-Encoded Yellow Fluorescent cAMP Indicator with an Expanded Dynamic Range for Dual-Color Imaging , 2014, PloS one.

[35]  T. Südhof,et al.  Latrophilins Function as Heterophilic Cell-adhesion Molecules by Binding to Teneurins , 2013, The Journal of Biological Chemistry.

[36]  T. Südhof,et al.  Membrane-Tethered Monomeric Neurexin LNS-Domain Triggers Synapse Formation , 2013, The Journal of Neuroscience.

[37]  M. Verhage,et al.  Neurobeachin regulates neurotransmitter receptor trafficking to synapses , 2013, The Journal of cell biology.

[38]  John D. Scott,et al.  Creating order from chaos: cellular regulation by kinase anchoring. , 2013, Annual review of pharmacology and toxicology.

[39]  J. Yates,et al.  FLRT Proteins Are Endogenous Latrophilin Ligands and Regulate Excitatory Synapse Development , 2012, Neuron.

[40]  Sheila V. Kusnoor,et al.  Comparison of Cbln1 and Cbln2 functions using transgenic and knockout mice , 2012, Journal of neurochemistry.

[41]  A. Tonevitsky,et al.  Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities , 2011, Proceedings of the National Academy of Sciences.

[42]  B. Sabatini,et al.  Glutamate induces de novo growth of functional spines in developing cortex , 2011, Nature.

[43]  Thomas C. Südhof,et al.  RIM Proteins Tether Ca2+ Channels to Presynaptic Active Zones via a Direct PDZ-Domain Interaction , 2011, Cell.

[44]  Masahito Yamagata,et al.  Many paths to synaptic specificity. , 2009, Annual review of cell and developmental biology.

[45]  E. Callaway.  Transneuronal circuit tracing with neurotropic viruses , 2008, Current Opinion in Neurobiology.

[46]  R. Stevens,et al.  GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function , 2007, Science.

[47]  R. Stevens,et al.  High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor , 2007, Science.

[48]  T. Südhof,et al.  Activity-Dependent Validation of Excitatory versus Inhibitory Synapses by Neuroligin-1 versus Neuroligin-2 , 2007, Neuron.

[49]  Thomas C. Südhof,et al.  Neuroligins Determine Synapse Maturation and Function , 2006, Neuron.

[50]  Cornelia I Bargmann,et al.  Synaptic Specificity Is Generated by the Synaptic Guidepost Protein SYG-2 and Its Receptor, SYG-1 , 2004, Cell.

[51]  T. Südhof,et al.  α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis , 2003, Nature.

[52]  T. Südhof,et al.  The G Protein-coupled Receptor CL1 Interacts Directly with Proteins of the Shank Family* , 2000, The Journal of Biological Chemistry.

[53]  E. Gundelfinger,et al.  The Calcium-independent Receptor for α-Latrotoxin from Human and Rodent Brains Interacts with Members of the ProSAP/SSTRIP/Shank Family of Multidomain Proteins* , 2000, The Journal of Biological Chemistry.

[54]  J. Beavo,et al.  Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  T. Südhof,et al.  α-Latrotoxin Receptor CIRL/Latrophilin 1 (CL1) Defines an Unusual Family of Ubiquitous G-protein-linked Receptors , 1998, The Journal of Biological Chemistry.

[56]  T. Südhof,et al.  alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. , 1998, The Journal of biological chemistry.

[57]  N. Sträter,et al.  Understanding the Structural Basis of Adhesion GPCR Functions. , 2016, Handbook of experimental pharmacology.

[58]  H. G. Vogel.  Guidelines for the Care and Use of Laboratory Animals , 2007 .

[59]  a -Latrotoxin Receptor CIRL/Latrophilin 1 (CL1) Defines an Unusual Family of Ubiquitous G-protein-linked Receptors G-PROTEIN , 2022 .