α-Latrotoxin and Its Receptors

  • Yuri A. Ushkaryov
  • Alexis Rohou
  • Shuzo Sugita
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 184)

α-Latrotoxin (α-LTX) from black widow spider venom induces exhaustive release of neurotransmitters from vertebrate nerve terminals and endocrine cells. This 130-kDa protein has been employed for many years as a molecular tool to study exocytosis. However, its action is complex: in neurons, α-LTX induces massive secretion both in the presence of extracellular Ca2+ (Ca2+ e) and in its absence; in endocrine cells, it usually requires Ca2+ e. To use this toxin for further dissection of secretory mechanisms, one needs an in-depth understanding of its functions. One such function that explains some α-LTX effects is its ability to form cation-permeable channels in artificial lipid bilayers. The mechanism of α-LTX pore formation, revealed by cryo-electron microscopy, involves toxin assembly into homotetrameric complexes which harbor a central channel and can insert into lipid membranes. However, in biological membranes, α-LTX cannot exert its actions without binding to specific receptors of the plasma membrane. Three proteins with distinct structures have been found to bind α-LTX: neurexin Iα, latrophilin 1, and receptor-like protein tyrosine phosphatase σ. Upon binding a receptor, α-LTX forms channels permeable to cations and small molecules; the toxin may also activate the receptor. To distinguish between the pore- and receptor-mediated effects, and to study structure-function relationships in the toxin, α-LTX mutants have been used.


Synaptic Vesicle Protein Tyrosine Phosphatase Transmitter Release Ankyrin Repeat Venom Gland 
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  1. Adam-Vizi V, Deri Z, Bors P et al (1993) Lack of involvement of [Ca2+ ]i in the external Ca2+ independent release of acetylcholine evoked by veratridine, ouabain and α-latrotoxin: possible role of [Na+ ]i . J Physiol Paris 87:43-50PubMedCrossRefGoogle Scholar
  2. Aicher B, Lerch MM, Muller T et al (1997) Cellular redistribution of protein tyrosine phosphatases LAR and PTPs by inducible proteolytic processing. J Cell Biol 138:681-96PubMedCrossRefGoogle Scholar
  3. Alete DE, Weeks ME, Hovanession AG et al (2006) Cell surface nucleolin on developing muscle is a potential ligand for the axonal receptor protein tyrosine phosphatase-s. FEBS J 273:4668-81PubMedCrossRefGoogle Scholar
  4. Andrade MA, Perez-Iratxeta C, Ponting CP (2001) Protein repeats: structures, functions, and evolution. J Struct Biol 134:117-31PubMedCrossRefGoogle Scholar
  5. Aristotle (350 B.C.) History of Animals. In Barnes J (ed) The complete works of Aristotle: The revised Oxford translation, 1984, Princeton, Princeton University PressGoogle Scholar
  6. Ashton AC, Rahman MA, Volynski KE et al (2000) Tetramerisation of α-latrotoxin by divalent cations is responsible for toxin-induced non-vesicular release and contributes to the Ca2+ dependent vesicular exocytosis from synaptosomes. Biochimie 82:453-68PubMedCrossRefGoogle Scholar
  7. Ashton AC, Volynski KE, Lelianova VG et al (2001) α-Latrotoxin, acting via two Ca2+ -dependent pathways, triggers exocytosis of two pools of synaptic vesicles. J Biol Chem 276:44695-703PubMedCrossRefGoogle Scholar
  8. Auger C, Marty A (1997) Heterogeneity of functional synaptic parameters among single release sites. Neuron 19:139-50PubMedCrossRefGoogle Scholar
  9. Augustine GJ, Charlton MP, Smith SJ (1987) Calcium action in synaptic transmitter release. Annu Rev Neurosci 10:633-93PubMedCrossRefGoogle Scholar
  10. Barnett DW, Liu J, Misler S (1996) Single-cell measurements of quantal secretion induced by αlatrotoxin from rat adrenal chromaffin cells: dependence on extracellular Ca2+ . Pflugers Arch 432:1039-46PubMedCrossRefGoogle Scholar
  11. Batt J, Asa S, Fladd C et al (2002) Pituitary, pancreatic and gut neuroendocrine defects in protein tyrosine phosphatase-sigma-deficient mice. Mol Endocrinol 16:155-69PubMedCrossRefGoogle Scholar
  12. Biederer T, S üdhof TC (2000) Mints as adaptors. Direct binding to neurexins and recruitment of munc18. J Biol Chem 275:39803-6PubMedCrossRefGoogle Scholar
  13. Bittner MA, Holz RW (2000) Latrotoxin stimulates secretion in permeabilized cells by regulating an intracellular Ca2+ - and ATP-dependent event: a role for protein kinase C. J Biol Chem 275:25351-7PubMedCrossRefGoogle Scholar
  14. Boehm S, Huck S (1998) Presynaptic inhibition by concanavalin A: are α-latrotoxin receptors involved in action potential-dependent transmitter release? J Neurochem 71:2421-30PubMedGoogle Scholar
  15. Boucard AA, Chubykin AA, Comoletti D et al (2005) A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron 48:229-36PubMedCrossRefGoogle Scholar
  16. Capogna M, Gahwiler BH, Thompson SM (1996) Calcium-independent actions of α-latrotoxin on spontaneous and evoked synaptic transmission in the hippocampus. J Neurophysiol 76:3149-58PubMedGoogle Scholar
  17. Capogna M, Volynski KE, Emptage NJ et al (2003) The α-latrotoxin mutant LTXN4C enhances spontaneous and evoked transmitter release in CA3 pyramidal neurons. J Neurosci 23:4044-53PubMedGoogle Scholar
  18. Cavalieri M, Corvaja N, Grasso A (1990) Immunocytological localization by monoclonal antibodies of α-latrotoxin in the venom gland of the spider Latrodectus tredecimguttatus. Toxicon 28:341-6PubMedCrossRefGoogle Scholar
  19. Ceccarelli B, Grohovaz F, Hurlbut WP (1979) Freeze-fracture studies of frog neuromuscular junctions during intense release of neurotransmitter. I. Effects of black widow spider venom and Ca2+ -free solutions on the structure of the active zone. J Cell Biol 81:163-77PubMedCrossRefGoogle Scholar
  20. Ceccarelli B, Hurlbut WP (1980) Ca2+ -dependent recycling of synaptic vesicles at the frog neuromuscular junction. J Cell Biol 87:297-303PubMedCrossRefGoogle Scholar
  21. Chanturia AN, Lishko VK (1992) Potential-dependent α-latrotoxin interaction with black lipid membranes. Toxicon 30:1059-64PubMedCrossRefGoogle Scholar
  22. Chen ML, Chen CH (2005) Microarray analysis of differentially expressed genes in rat frontal cortex under chronic risperidone treatment. Neuropsychopharmacology 30:268-77PubMedCrossRefGoogle Scholar
  23. Chih B, Gollan L, Scheiffele P (2006) Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex. Neuron 51:171-8PubMedCrossRefGoogle Scholar
  24. Comoletti D, De JA, Jennings LL et al (2004) The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci 24:4889-93PubMedCrossRefGoogle Scholar
  25. Comoletti D, Flynn RE, Boucard AA et al (2006) Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for β-neurexins. Biochemistry 45:12816-27PubMedCrossRefGoogle Scholar
  26. D’Amour F, Becker FE, van Riper W (1936) The black widow spider. Q Rev Biol 11:123-60CrossRefGoogle Scholar
  27. Davletov BA, Krasnoperov V, Hata Y et al (1995) High affinity binding of α-latrotoxin to recombinant neurexin Iα. J Biol Chem 270:23903-5PubMedCrossRefGoogle Scholar
  28. Davletov BA, Meunier FA, Ashton AC et al (1998) Vesicle exocytosis stimulated by α-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+ . EMBO J 17:3909-20PubMedCrossRefGoogle Scholar
  29. Davletov BA, Shamotienko OG, Lelianova VG et al (1996) Isolation and biochemical characteri- zation of a Ca2+ -independent α-latrotoxin-binding protein. J Biol Chem 271:23239-45PubMedCrossRefGoogle Scholar
  30. Dean C, Scholl FG, Choih J et al (2003) Neurexin mediates the assembly of presynaptic terminals. Nat Neurosci 6:708-16PubMedCrossRefGoogle Scholar
  31. Deri Z, Adam-Vizi V (1993) Detection of intracellular free Na+ concentration of synaptosomes by a fluorescent indicator, Na+ -binding benzofuran isophthalate: the effect of veratridine, ouabain, and α-latrotoxin. J Neurochem 61:818-25PubMedCrossRefGoogle Scholar
  32. Deri Z, Bors P, Adam-Vizi V (1993) Effect of α-latrotoxin on acetylcholine release and intracellular Ca2+ concentration in synaptosomes: Na+ -dependent and Na+ -independent components. J Neurochem 60:1065-72PubMedCrossRefGoogle Scholar
  33. Dresbach T, Neeb A, Meyer G et al (2004) Synaptic targeting of neuroligin is independent of neurexin and SAP90/PSD95 binding. Mol Cell Neurosci 27 227-35PubMedGoogle Scholar
  34. Duan ZG, Yan XJ, He XZ et al (2006) Extraction and protein component analysis of venom from the dissected venom glands of Latrodectus tredecimguttatus. Comp Biochem Physiol B Biochem Mol Biol 145:350-7PubMedCrossRefGoogle Scholar
  35. Dudanova I, Sedej S, Ahmad M et al (2006) Important contribution of α-neurexins to Ca2+ triggered exocytosis of secretory granules. J Neurosci 26:10599-613PubMedCrossRefGoogle Scholar
  36. Fesce R, Segal JR, Ceccarelli B et al (1986) Effects of black widow spider venom and Ca2+ on quantal secretion at the frog neuromuscular junction. J Gen Physiol 88:59-81PubMedCrossRefGoogle Scholar
  37. Filippov AK, Tertishnikova SM, Alekseev AE et al (1994) Mechanism of α-latrotoxin action as revealed by patch-clamp experiments on Xenopus oocytes injected with rat brain messenger RNA. Neuroscience 61:179-89PubMedCrossRefGoogle Scholar
  38. Finkelstein A, Rubin LL, Tzeng M-C (1976) Black widow spider venom: effect of purified toxin on lipid bilayer membranes. Science 193:1009-11PubMedCrossRefGoogle Scholar
  39. Fredriksson R, Schioth HB (2005) The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67:1414-25PubMedCrossRefGoogle Scholar
  40. Frontali N, Ceccarelli B, Gorio A et al (1976) Purification from black widow spider venom of a protein factor causing the depletion of synaptic vesicles at neuromuscular junctions. J Cell Biol 68:462-79PubMedCrossRefGoogle Scholar
  41. Geppert M, Khvotchev M, Krasnoperov V et al (1998) Neurexin Iα is a major α-latrotoxin receptor that cooperates in α-latrotoxin action. J Biol Chem 273:1705-10PubMedCrossRefGoogle Scholar
  42. Grasso A, Alema S, Rufini S et al (1980) Black widow spider toxin-induced calcium fluxes and transmitter release in a neurosecretory cell line. Nature 283:774-6PubMedCrossRefGoogle Scholar
  43. Grasso A, Mercanti-Ciotti MT (1993) The secretion of amino acid transmitters from cerebellar primary cultures probed by α-latrotoxin. Neuroscience 54:595-604PubMedCrossRefGoogle Scholar
  44. Grasso A, Rufini S, Senni I (1978) Concanavalin A blocks black widow spider toxin stimulation of transmitter release from synaptosomes. FEBS Lett 85:241-4PubMedCrossRefGoogle Scholar
  45. Grasso A, Senni MI (1979) A toxin purified from the venom of black widow spider affects the uptake and release of radioactive γ -amino butyrate and N-epinephrine from rat brain synaptosomes. Eur J Biochem 102:337-44PubMedCrossRefGoogle Scholar
  46. Gray JX, Haino M, Roth MJ et al (1996) CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation. J Immunol 157:5438-47PubMedGoogle Scholar
  47. Grishin EV (1998) Black widow spider toxins: the present and the future. Toxicon 36:1693-1701 Grishin EV, Himmelreich NH, Pluzhnikov KA et al (1993) Modulation of functional activities of the neurotoxin from black widow spider venom. FEBS Lett 336:205-7CrossRefGoogle Scholar
  48. Gutman GA, Chandy KG, Grissmer S et al (2005) International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 57:473-508PubMedCrossRefGoogle Scholar
  49. Harmar AJ (2001) Family-B G-protein-coupled receptors. Genome Biol 2:3013.1-3013.10CrossRefGoogle Scholar
  50. Hata Y, Butz S, S üdhof TC (1996) CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci 16:2488-94PubMedGoogle Scholar
  51. Hayflick JS (2000) A family of heptahelical receptors with adhesion-like domains: a marriage between two super families. J Recept Signal Transduct Res 20:119-31PubMedCrossRefGoogle Scholar
  52. Hlubek M, Tian D, Stuenkel EL (2003) Mechanism of α-latrotoxin action at nerve endings of neurohypophysis. Brain Res 992:30-42PubMedCrossRefGoogle Scholar
  53. Hlubek MD, Stuenkel EL, Krasnoperov VG et al (2000) Calcium-independent receptor for α-latrotoxin and neurexin Iα facilitate toxin-induced channel formation: evidence that channel formation results from tethering of toxin to membrane. Mol Pharmacol 57:519-28PubMedGoogle Scholar
  54. Hurlbut WP, Ceccarelli B (1979) Use of black widow spider venom to study the release of neurotransmitters. Adv Cytopharmacol 3:87-115:87-115PubMedGoogle Scholar
  55. Hurlbut WP, Chieregatti E, Valtorta F et al (1994) α-Latrotoxin channels in neuroblastoma cells. J Membr Biol 138:91-102PubMedGoogle Scholar
  56. Ichtchenko K, Bittner MA, Krasnoperov V et al (1999) A novel ubiquitously expressed α-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors. J Biol Chem 274:5491-8PubMedCrossRefGoogle Scholar
  57. Ichtchenko K, Hata Y, Nguyen T et al (1995) Neuroligin 1: a splice site-specific ligand for β-neurexins. Cell 81:435-43PubMedCrossRefGoogle Scholar
  58. Ichtchenko K, Khvotchev M, Kiyatkin N et al (1998) α-Latrotoxin action probed with recombinant toxin: receptors recruit α-latrotoxin but do not transduce an exocytotic signal. EMBO J 17:6188-99PubMedCrossRefGoogle Scholar
  59. Ichtchenko K, Nguyen T, S üdhof TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem 271:2676-82PubMedCrossRefGoogle Scholar
  60. Kattenstroth G, Tantalaki E, S üdhof TC et al (2004) Postsynaptic N-methyl-D-aspartate receptor function requires α-neurexins. Proc Natl Acad Sci U S A 101:2607-2612PubMedCrossRefGoogle Scholar
  61. Khvotchev M, Lonart G, S üdhof TC (2000) Role of calcium in neurotransmitter release evoked by α-latrotoxin or hypertonic sucrose. Neuroscience 101: 793-802PubMedCrossRefGoogle Scholar
  62. Kiyatkin NI, Dulubova IE, Chekhovskaya IA et al (1990) Cloning and structure of cDNA encoding α-latrotoxin from black widow spider venom. FEBS Lett 270:127-31PubMedCrossRefGoogle Scholar
  63. Kiyatkin NI, Kulikovskaya IM, Grishin EV et al (1995) Functional characterization of black widow spider neurotoxins synthesised in insect cells. Eur J Biochem 230:854-9PubMedCrossRefGoogle Scholar
  64. Krasil’nikov OV, Sabirov RZ, Chanturiia AN et al (1988) [Conductivity and diameter of latrotoxin channels in lipid bilayers]. Ukr Biokhim Zh 60:67-71PubMedGoogle Scholar
  65. Krasil’nikov OV, Ternovskii VI, Tashmukhamedov BA (1982) [Channel formation properties of black widow venom]. Biofizika 27:72-5PubMedGoogle Scholar
  66. Krasil’nikov OV, Sabirov RZ (1992) Comparative analysis of latrotoxin channels of different conductance in planar lipid bilayers. Evidence for cluster organization. Biochim Biophys Acta 1112:124-8CrossRefGoogle Scholar
  67. Krasnoperov V, Bittner MA, Holz RW et al (1999) Structural requirements for α-latrotoxin binding and α-latrotoxin-stimulated secretion. A study with calcium-independent receptor of α-latrotoxin (CIRL) deletion mutants. J Biol Chem 274:3590-6PubMedCrossRefGoogle Scholar
  68. Krasnoperov V, Lu Y, Buryanovsky L et al (2002a) Post-translational proteolytic processing of the calcium-independent receptor of α-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. J Biol Chem 277:46518-26CrossRefGoogle Scholar
  69. Krasnoperov VG, Beavis R, Chepurny OG et al (1996) The calcium-independent receptor of α-latrotoxin is not a neurexin. Biochem Biophys Res Commun 227:868-75PubMedCrossRefGoogle Scholar
  70. Krasnoperov VG, Bittner MA, Beavis R et al (1997) α-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron 18:925-37PubMedCrossRefGoogle Scholar
  71. Krasnoperov VG, Bittner MA, Mo W et al (2002b) Protein tyrosine phosphatase-s is a novel member of the functional family of α-latrotoxin receptors. J Biol Chem 277:35887-95CrossRefGoogle Scholar
  72. Kreienkamp HJ, Zitzer H, Gundelfinger ED et al (2000) The calcium-independent re-ceptor for α-latrotoxin from human and rodent brains interacts with members of the ProSAP/SSTRIP/Shank family of multidomain proteins. J Biol Chem 275:32387-90PubMedCrossRefGoogle Scholar
  73. Lajus S, Lang J (2006) Splice variant 3, but not 2 of receptor protein-tyrosine phosphatase s can mediate stimulation of insulin-secretion by α-latrotoxin. J Cell Biochem 98:1552-9PubMedCrossRefGoogle Scholar
  74. Lajus S, Vacher P, Huber D et al (2006) α-Latrotoxin induces exocytosis by inhibition of voltagedependent K+ channels and by stimulation of L-type Ca2+ channels via latrophilin in β-cells. J Biol Chem 281:5522-31PubMedCrossRefGoogle Scholar
  75. Lang J, Ushkaryov Y, Grasso A et al (1998) Ca2+ -independent insulin exocytosis induced by α-latrotoxin requires latrophilin, a G protein-coupled receptor. EMBO J 17:648-57PubMedCrossRefGoogle Scholar
  76. Lelianova VG, Davletov BA, Sterling A et al (1997) α-Latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors. J Biol Chem 272:21504-8PubMedCrossRefGoogle Scholar
  77. Levinson JN, Chery N, Huang K et al (2005) Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-1β in neuroligin-induced synaptic specificity. J Biol Chem 280:17312-19PubMedCrossRefGoogle Scholar
  78. Li G, Lee D, Wang L et al (2005) N-terminal insertion and C-terminal ankyrin-like repeats of α-latrotoxin are critical for Ca2+ -dependent exocytosis. J Neurosci 25:10188-97PubMedCrossRefGoogle Scholar
  79. Lindsay AR, Tinker A, Williams AJ (1994) How does ryanodine modify ion handling in the sheep cardiac sarcoplasmic reticulum Ca2+ -release channel? J Gen Physiol 104:425-47PubMedCrossRefGoogle Scholar
  80. Lishko VK, Terletskaya YT, Trikash IO (1990) Fusion of negatively charged phospholipid-vesicles by α-latrotoxin. FEBS Letters 266:99-101PubMedCrossRefGoogle Scholar
  81. Liu J, Misler S (1998) α-Latrotoxin alters spontaneous and depolarization-evoked quantal release from rat adrenal chromaffin cells: evidence for multiple modes of action. J Neurosci 18:6113-25PubMedGoogle Scholar
  82. Liu J, Wan Q, Lin X et al (2005) α-Latrotoxin modulates the secretory machinery via receptormediated activation of protein kinase C. Traffic 6:756-65PubMedCrossRefGoogle Scholar
  83. Long SB, Campbell EB, Mackinnon R (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309:897-903PubMedCrossRefGoogle Scholar
  84. Longenecker HE, Hurlbut WP, Mauro A et al (1970) Effects of black widow spider venom on the frog neuromuscular junction. Effects on end-plate potential, miniature end-plate potential and nerve terminal spike. Nature 225:701-3PubMedCrossRefGoogle Scholar
  85. Loria PM, Hodgkin J, Hobert O (2004) A conserved postsynaptic transmembrane protein affecting neuromuscular signalling in Caenorhabditis elegans. J Neurosci 24:2191-2201PubMedCrossRefGoogle Scholar
  86. Lunev AV, Demin VV, Zaitsev OI et al (1991) [Electron microscopy of α-latrotoxin from the venom of the black widow spider Latrodectus mactans tredecimguttatus]. Bioorg Khim 17:1021-6PubMedGoogle Scholar
  87. Matsushita H, Lelianova VG, Ushkaryov YA (1999) The latrophilin family: multiply spliced G protein-coupled receptors with differential tissue distribution. FEBS Lett 443:348-52PubMedCrossRefGoogle Scholar
  88. Matteoli M, Haimann C, Torri-Tarelli F et al (1988) Differential effect of α-latrotoxin on exocytosis from small synaptic vesicles and from large dense-core vesicles containing calcitonin generelated peptide at the frog neuromuscular junction. Proc Natl Acad Sci U S A 85:7366-70PubMedCrossRefGoogle Scholar
  89. McLean J, Batt J, Doering LC et al (2002) Enhanced rate of nerve regeneration and directional errors after sciatic nerve injury in receptor protein tyrosine phosphatase sigma knock-out mice. J Neurosci 22:5481-91PubMedGoogle Scholar
  90. McMahon HT, Rosenthal L, Meldolesi J et al (1990) α-Latrotoxin releases both vesicular and cytoplasmic glutamate from isolated nerve terminals. J Neurochem 55:2039-47PubMedCrossRefGoogle Scholar
  91. Meathrel K, Adamek T, Batt J et al (2002) Protein tyrosine phosphatase sigma-deficient mice show aberrant cytoarchitecture and structural abnormalities in the central nervous system. J Neurosci Res 70:24-35PubMedCrossRefGoogle Scholar
  92. Mee CJ, Tomlinson SR, Perestenko PV et al (2004) Latrophilin is required for toxicity of black widow spider venom in Caenorhabditis elegans. Biochem J 378:185-91PubMedCrossRefGoogle Scholar
  93. Meiri H, Erulkar SD, Lerman T et al (1981) The action of the sodium ionophore, monensin, or transmitter release at the frog neuromuscular junction. Brain Res 204:204-8PubMedCrossRefGoogle Scholar
  94. Meldolesi J, Huttner WB, Tsien RY et al (1984) Free cytoplasmic Ca2+ and neurotransmitter release: studies on PC12 cells and synaptosomes exposed to α-latrotoxin. Proc Natl Acad Sci U S A 81:620-4PubMedCrossRefGoogle Scholar
  95. Meldolesi J, Madeddu L, Torda M et al (1983) The effect of α-latrotoxin on the neurosecretory PC12 cell line: studies on toxin binding and stimulation of transmitter release. Neuroscience 10:997-1009PubMedCrossRefGoogle Scholar
  96. Michaely P, Tomchick DR, Machius M et al (2002) Crystal structure of a 12 ANK repeat stack from human ankyrinR. EMBO J 21:6387-96PubMedCrossRefGoogle Scholar
  97. Michelena P, de la Fuente MT, Vega T et al (1997) Drastic facilitation by α-latrotoxin of bovine chromaffin cell exocytosis without measurable enhancement of Ca2+ entry or [Ca2+ ]i . J Physiol (Lond) 502:481-96CrossRefGoogle Scholar
  98. Mironov SL, Sokolov Y, Chanturiya AN et al (1986) Channels produced by spider venoms in bilayer lipid membrane: mechanisms of ion transport and toxic action. Biochim Biophys Acta 862:185-98PubMedCrossRefGoogle Scholar
  99. Misler S, Falke LC (1987) Dependence on multivalent cations of quantal release of transmitter induced by black widow spider venom. Am J Physiol 253:C469-76PubMedGoogle Scholar
  100. Misler S, Hurlbut WP (1979) Action of black widow spider venom on quantized release of acetylcholine at the frog neuromuscular junction: dependence upon external Mg2+ . Proc Natl Acad Sci U S A 76:991-5PubMedCrossRefGoogle Scholar
  101. Missler M, Fernandez-Chacon R, S üdhof TC (1998a) The making of neurexins. J Neurochem 71:1339-47CrossRefGoogle Scholar
  102. Missler M, Hammer RE, S üdhof TC (1998b) Neurexophilin binding to α-neurexins. A single LNS domain functions as an independently folding ligand-binding unit. J Biol Chem 273:34716-723CrossRefGoogle Scholar
  103. Missler M, S üdhof TC (1998) Neurexins: three genes and 1001 products. Trends Genet 14:20-6PubMedCrossRefGoogle Scholar
  104. Missler M, Zhang W, Rohlmann A et al (2003) α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423:939-48PubMedCrossRefGoogle Scholar
  105. Nguyen T, S üdhof TC (1997) Binding properties of neuroligin 1 and neurexin 1β reveal function as heterophilic cell adhesion molecules. J Biol Chem 272:26032-9PubMedCrossRefGoogle Scholar
  106. Nicholls DG, Rugolo M, Scott IG et al (1982) α-Latrotoxin of black widow spider venom depolarizes the plasma membrane, induces massive calcium influx, and stimulates transmitter release in guinea pig brain synaptosomes. Proc Natl Acad Sci U S A 79:7924-8PubMedCrossRefGoogle Scholar
  107. Nishimura W, Iizuka T, Hirabayashi S et al (2000) Localization of BAI-associated protein1/ membrane-associated guanylate kinase-1 at adherens junctions in normal rat kidney cells: polarized targeting mediated by the carboxyl-terminal PDZ domains. J Cell Physiol 185:358-65PubMedCrossRefGoogle Scholar
  108. Occhi G, Rampazzo A, Beffagna G et al (2002) Identification and characterization of heart-specific splicing of human neurexin 3 mRNA (NRXN3). Biochem Biophys Res Commun 298:151-5PubMedCrossRefGoogle Scholar
  109. Orlova EV, Rahman MA, Gowen B et al (2000) Structure of α-latrotoxin oligomers reveals that divalent cation-dependent tetramers form membrane pores. Nat Struct Biol 7:48-53PubMedCrossRefGoogle Scholar
  110. Pescatori M, Bradbury A, Bouet F et al (1995) The cloning of a cDNA encoding a protein (latrodectin) which co-purifies with the α-latrotoxin from the black widow spider Latrodectus tredecimguttatus (Theridiidae). Eur J Biochem 230:322-8PubMedCrossRefGoogle Scholar
  111. Petrenko AG, Kovalenko VA, Shamotienko OG et al (1990) Isolation and properties of the α-latrotoxin receptor. EMBO J 9:2023-7PubMedGoogle Scholar
  112. Petrenko AG, Lazaryeva VD, Geppert M et al (1993) Polypeptide composition of the α-latrotoxin receptor. High affinity binding protein consists of a family of related high molecular weight polypeptides complexed to a low molecular weight protein. J Biol Chem 268:1860-7PubMedGoogle Scholar
  113. Petrenko AG, Ullrich B, Missler M et al (1996) Structure and evolution of neurexophilin. J Neurosci 16:4360-9PubMedGoogle Scholar
  114. Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera - a visualization system for exploratory research and analysis. J Comput Chem 25:1605-12PubMedCrossRefGoogle Scholar
  115. Picotti GB, Bondiolotti GP, Meldolesi J (1982) Peripheral catecholamine release by α-latrotoxin in the rat. Naunyn Schmiedebergs Arch Pharmacol 320:224-9PubMedCrossRefGoogle Scholar
  116. Pulido R, Serra-Pages C, Tang M et al (1995) The LAR/PTPd/PTPs subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTPd, and PTPs isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proc Natl Acad Sci U S A 92:11686-90PubMedCrossRefGoogle Scholar
  117. Rahman MA, Ashton AC, Meunier FA et al (1999) Norepinephrine exocytosis stimulated by α-latrotoxin requires both external and stored Ca2+ and is mediated by latrophilin, G proteins and phospholipase C. Phil Trans R Soc Lond B 354:379-86CrossRefGoogle Scholar
  118. Robello M (1989) Dependence of the conductance of the α-latrotoxin channel on applied potential and potassium concentration. Biochim Biophys Acta 978:179-84PubMedCrossRefGoogle Scholar
  119. Robello M, Fresia M, Maga L et al (1987) Permeation of divalent cations through α-latrotoxin channels in lipid bilayers: steady-state current-voltage relationships. J Membr Biol 95:55-62PubMedCrossRefGoogle Scholar
  120. Robello M, Rolandi R, Alema S et al (1984) Trans-bilayer orientation and voltage-dependence of α-latrotoxin-induced channels. Proceedings of the Royal Society of London Series B-Biological Sciences 220:477-87CrossRefGoogle Scholar
  121. Rosenthal L, Meldolesi J (1989) α-Latrotoxin and related toxins. Pharmacol Ther 42:115-34PubMedCrossRefGoogle Scholar
  122. Rosenthal L, Zacchetti D, Madeddu L et al (1990) Mode of action of α-latrotoxin: role of divalent cations in Ca2+ -dependent and Ca2+ -independent effects mediated by the toxin. Mol Pharmacol 38:917-23PubMedGoogle Scholar
  123. Ruhe JE, Streit S, Hart S et al (2006) EGFR signalling leads to downregulation of PTP-LAR via TACE-mediated proteolytic processing. Cell Signal 18:1515-27PubMedCrossRefGoogle Scholar
  124. Sajnani-Perez G, Chilton JK, Aricescu AR et al (2003) Isoform-specific binding of the tyrosine phosphatase PTPs to a ligand in developing muscle. Mol Cell Neurosci 22:37-48PubMedCrossRefGoogle Scholar
  125. Scheer H, Prestipino G, Meldolesi J (1986) Reconstitution of the purified α-latrotoxin receptor in liposomes and planar lipid membranes. Clues to the mechanism of toxin action. EMBO J 5:2643-8PubMedGoogle Scholar
  126. Scheer HW (1989) Interactions between α-latrotoxin and trivalent cations in rat striatal synaptosomal preparations. J Neurochem 52:1590-7PubMedCrossRefGoogle Scholar
  127. Scheiffele P, Fan J, Choih J et al (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101:657-69PubMedCrossRefGoogle Scholar
  128. Sedgwick SG, Smerdon SJ (1999) The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem Sci 24:311-16PubMedCrossRefGoogle Scholar
  129. Serra-Pages C, Saito H, Streuli M (1994) Mutational analysis of proprotein processing, subunit association, and shedding of the LAR transmembrane protein tyrosine phosphatase. J Biol Chem 269:23632-41PubMedGoogle Scholar
  130. Serysheva II, Hamilton SL, Chiu W et al (2005) Structure of Ca2+ release channel at 14A˚ resolution. J Mol Biol 345:427-31PubMedCrossRefGoogle Scholar
  131. Silva AM, Liu-Gentry J, Dickey AS et al (2005) α-Latrotoxin increases spontaneous and depolarization-evoked exocytosis from pancreatic islet β-cells. J Physiol 565:783-99PubMedCrossRefGoogle Scholar
  132. Siu R, Fladd C, Rotin D (2006) N-cadherin is an in vivo substrate for PTPs and participates in PTPs-mediated inhibition of axon growth. Mol Cell Biol 27:208-19PubMedCrossRefGoogle Scholar
  133. Smith DS, Russell FE (1966) Structure of the venom gland of the black widow spider Latrodectus mactans. A preliminary light and electron microscopic study. In Russell FE, Saunders PR (eds) Animal Toxins, Oxford, Pergamon, pp 1-15Google Scholar
  134. Snyder DA, Rivers AM, Yokoe H et al (1991) Olfactomedin: purification, characterization, and localization of a novel olfactory glycoprotein. Biochemistry 30:9143-53PubMedCrossRefGoogle Scholar
  135. Sokolov YV, Chanturia AN, Lishko VK (1987) Latrotoxin-induced fusion of liposomes with bilayer phospholipid-membranes. Biochimica et Biophysica Acta 900:295-9PubMedCrossRefGoogle Scholar
  136. Song JY, Ichtchenko K, S üdhof TC et al (1999) Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci U S A 96:1100-5PubMedCrossRefGoogle Scholar
  137. Stacey M, Lin HH, Gordon S et al (2000) LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem Sci 25:284-9PubMedCrossRefGoogle Scholar
  138. Storchak LG, Pashkov VN, Pozdnyakova NG et al (1994) α-Latrotoxin-stimulated GABA release can occur in Ca2+ -free, Na+ -free medium. FEBS Lett 351:267-70PubMedCrossRefGoogle Scholar
  139. S üdhof TC (2001) α-Latrotoxin and its receptors: neurexins and CIRL/latrophilins. Annu Rev Neurosci 24:933-62CrossRefGoogle Scholar
  140. Sugita S, Ichtchenko K, Khvotchev M et al (1998) α-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J Biol Chem 273:32715-24PubMedCrossRefGoogle Scholar
  141. Sugita S, Khvochtev M, S üdhof TC (1999) Neurexins are functional α-latrotoxin receptors. Neuron 22:489-96PubMedCrossRefGoogle Scholar
  142. Thompson KM, Uetani N, Manitt C et al (2003) Receptor protein tyrosine phosphatase sigma inhibits axonal regeneration and the rate of axon extension. Mol Cell Neurosci 23:681-92PubMedCrossRefGoogle Scholar
  143. Tobaben S, S üdhof TC, Stahl B (2002) Genetic analysis of α-latrotoxin receptors reveals functional interdependence of CIRL/latrophilin 1 and neurexin Iα. J Biol Chem 277:6359-65PubMedCrossRefGoogle Scholar
  144. Tobaben S, S üdhof TC, Stahl B (2000) The G protein-coupled receptor CL1 interacts directly with proteins of the Shank family. J Biol Chem 275:36204-10PubMedCrossRefGoogle Scholar
  145. Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7:833-46PubMedCrossRefGoogle Scholar
  146. Tsang CW, Elrick DB, Charlton MP (2000) α-Latrotoxin releases calcium in frog motor nerve terminals. J Neurosci 20:8685-92PubMedGoogle Scholar
  147. Tse FW, Tse A (1999) α-Latrotoxin stimulates inward current, rise in cytosolic calcium concentration, and exocytosis in pituitary gonadotropes. Endocrinology 140:3025-33PubMedCrossRefGoogle Scholar
  148. Tzeng MC, Cohen RS, Siekevitz P (1978) Release of neurotransmitters and depletion of synaptic vesicles in cerebral cortex slices by α-latrotoxin from black widow spider venom. Proc Natl Acad Sci U S A 75:4016-20PubMedCrossRefGoogle Scholar
  149. Tzeng MC, Siekevitz P (1979) The binding interaction between α-latrotoxin from black widow spider venom and a dog cerebral cortex synaptosomal membrane preparation. J Neurochem 33:263-74PubMedCrossRefGoogle Scholar
  150. Ullrich B, Ushkaryov YA, S üdhof TC (1995) Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14:497-507PubMedCrossRefGoogle Scholar
  151. Umbach JA, Grasso A, Zurcher SD et al (1998) Electrical and optical monitoring of α-latrotoxin action at Drosophila neuromuscular junctions. Neuroscience 87:913-24PubMedCrossRefGoogle Scholar
  152. Ushkaryov YA, Hata Y, Ichtchenko K et al (1994) Conserved domain structure of β-neurexins. Unusual cleaved signal sequences in receptor-like neuronal cell-surface proteins. J Biol Chem 269:11987-92PubMedGoogle Scholar
  153. Ushkaryov YA, Petrenko AG, Geppert M et al (1992) Neurexins: synaptic cell surface proteins related to the α-latrotoxin receptor and laminin. Science 257:50-6PubMedCrossRefGoogle Scholar
  154. Ushkaryov YA, S üdhof TC (1993) Neurexin IIIα: extensive alternative splicing generates membrane-bound and soluble forms. Proc Natl Acad Sci U S A 90:6410-14PubMedCrossRefGoogle Scholar
  155. Ushkaryov YA, Volynski KE, Ashton AC (2004) The multiple actions of black widow spider toxins and their selective use in neurosecretion studies. Toxicon 43:527-42PubMedCrossRefGoogle Scholar
  156. Van Renterghem C, Iborra C, Martin-Moutot N et al (2000) α-Latrotoxin forms calcium-permeable membrane pores via interactions with latrophilin or neurexin. Eur J Neurosci 12:3953-62PubMedCrossRefGoogle Scholar
  157. Varoqueaux F, Aramuni G, Rawson RL et al (2006) Neuroligins determine synapse maturation and function. Neuron 51:741-54PubMedCrossRefGoogle Scholar
  158. Varoqueaux F, Jamain S, Brose N (2004) Neuroligin 2 is exclusively localized to inhibitory synapses. Eur J Cell Biol 83:449-56PubMedCrossRefGoogle Scholar
  159. Verhage M, Maia AS, Plomp JJ et al (2000) Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287 864-9PubMedCrossRefGoogle Scholar
  160. Vicentini LM, Meldolesi J (1984) α Latrotoxin of black widow spider venom binds to a specific receptor coupled to phosphoinositide breakdown in PC12 cells. Biochem Biophys Res Commun 121:538-44PubMedCrossRefGoogle Scholar
  161. Volkova TM, Pluzhnikov KA, Woll PG et al (1995) Low-molecular-weight components from black-widow spider venom. Toxicon 33:483-9PubMedCrossRefGoogle Scholar
  162. Volynski KE, Capogna M, Ashton AC et al (2003) Mutant α-latrotoxin (LTXN4C ) does not form pores and causes secretion by receptor stimulation. This action does not require neurexins. J Biol Chem 278:31058-66PubMedCrossRefGoogle Scholar
  163. Volynski KE, Nosyreva ED, Ushkaryov YA et al (1999) Functional expression of α-latrotoxin in baculovirus system. FEBS Lett 442:25-8PubMedCrossRefGoogle Scholar
  164. Volynski KE, Silva JP, Lelianova VG et al (2004) Latrophilin fragments behave as independent proteins that associate and signal on binding of LTXN4C . EMBO J 23:4423-33PubMedCrossRefGoogle Scholar
  165. Volynski KV, Meunier FA, Lelianova VG et al (2000) Latrophilin, neurexin and their signallingdeficient mutants facilitate α-latrotoxin insertion into membranes but are not involved in pore formation. J Biol Chem 275:41175-83PubMedCrossRefGoogle Scholar
  166. Wanke E, Ferroni A, Gattanini P et al (1986) α-Latrotoxin of the black widow spider venom opens a small, non-closing cation channel. Biochem Biophys Res Commun 134:320-5PubMedCrossRefGoogle Scholar
  167. Watanabe O, Meldolesi J (1983) The effects of α-latrotoxin of black widow spider venom on synaptosome ultrastructure. A morphometric analysis correlating its effects on transmitter release. J Neurocytol 12:517-31PubMedCrossRefGoogle Scholar
  168. Willson J, Amliwala K, Davis A et al (2004) Latrotoxin receptor signalling engages the UNC-13-dependent vesicle-priming pathway in C. elegans. Curr Biol 14:1374-9PubMedCrossRefGoogle Scholar
  169. Yan H, Grossman A, Wang H et al (1993) A novel receptor tyrosine phosphatase-s that is highly expressed in the nervous system. J Biol Chem 268:24880-6PubMedGoogle Scholar
  170. Zhang W, Rohlmann A, Sargsyan V et al (2005) Extracellular domains of α-neurexins participate in regulating synaptic transmission by selectively affecting N- and P/Q-type Ca2+ channels. J Neurosci 25:4330-42PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Yuri A. Ushkaryov
    • 1
  • Alexis Rohou
    • 1
  • Shuzo Sugita
    • 2
  1. 1.Division of Cell and Molecular BiologyImperial College LondonLondonUK
  2. 2.Division of Cellular and Molecular BiologyToronto Western Research InstituteToronto, OntarioCanada

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