TY - JOUR
T1 - Neurexin Iα is a major α-latrotoxin receptor that cooperates in α- latrotoxin action
AU - Geppert, Martin
AU - Khvotchev, Mikhail
AU - Krasnoperov, Valery
AU - Goda, Yukiko
AU - Missler, Markus
AU - Hammer, Robert E
AU - Ichtchenko, Konstantin
AU - Petrenko, Alexander G.
AU - Südhof, Thomas C.
PY - 1998/1/16
Y1 - 1998/1/16
N2 - α-Latrotoxin is a potent neurotoxin from black widow spider venom that binds to presynaptic receptors and causes massive neurotransmitter release. A surprising finding was the biochemical description of two distinct cell surface proteins that bind α-latrotoxin with nanomolar affinities; Neurexin Iα binds α-latrotoxin in a Ca2+-dependent manner, and CIRL/latrophilin binds in a Ca2+-independent manner. We have now generated and analyzed mice that lack neurexin Iα tot est its importance in α-latrotoxin action. α- Latrotoxin binding to brain membranes from mutant mice was decreased by almost 50% compared with wild type membranes; the decrease was almost entirely due to a loss of Ca2+-dependent α-latrotoxin binding sites. In cultured hippocampal neurons, α-latrotoxin was still capable of activating neurotransmission in the absence of neurexin Iα. Direct measurements of [3H] glutamate release from synaptosomes, however, showed a major decrease in the amount of release triggered by α-latrotoxin in the presence of Ca2+. Thus neurexin Iα is not essential for α-latrotoxin action but contributes to α-latrotoxin action when Ca2+ is present. Viewed as a whole, our results show that mice contain two distinct types of α-latrotoxin receptors with similar affinities and abundance but different properties and functions. The action of α-latrotoxin may therefore be mediated by independent parallel pathways, of which the CIRL/latrophilin pathway is sufficient for neurotransmitter release, whereas the neurexin Iα pathway contributes to the Ca2+-dependent action of α-latrotoxin.
AB - α-Latrotoxin is a potent neurotoxin from black widow spider venom that binds to presynaptic receptors and causes massive neurotransmitter release. A surprising finding was the biochemical description of two distinct cell surface proteins that bind α-latrotoxin with nanomolar affinities; Neurexin Iα binds α-latrotoxin in a Ca2+-dependent manner, and CIRL/latrophilin binds in a Ca2+-independent manner. We have now generated and analyzed mice that lack neurexin Iα tot est its importance in α-latrotoxin action. α- Latrotoxin binding to brain membranes from mutant mice was decreased by almost 50% compared with wild type membranes; the decrease was almost entirely due to a loss of Ca2+-dependent α-latrotoxin binding sites. In cultured hippocampal neurons, α-latrotoxin was still capable of activating neurotransmission in the absence of neurexin Iα. Direct measurements of [3H] glutamate release from synaptosomes, however, showed a major decrease in the amount of release triggered by α-latrotoxin in the presence of Ca2+. Thus neurexin Iα is not essential for α-latrotoxin action but contributes to α-latrotoxin action when Ca2+ is present. Viewed as a whole, our results show that mice contain two distinct types of α-latrotoxin receptors with similar affinities and abundance but different properties and functions. The action of α-latrotoxin may therefore be mediated by independent parallel pathways, of which the CIRL/latrophilin pathway is sufficient for neurotransmitter release, whereas the neurexin Iα pathway contributes to the Ca2+-dependent action of α-latrotoxin.
UR - http://www.scopus.com/inward/record.url?scp=0031938886&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031938886&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.3.1705
DO - 10.1074/jbc.273.3.1705
M3 - Article
C2 - 9430716
AN - SCOPUS:0031938886
SN - 0021-9258
VL - 273
SP - 1705
EP - 1710
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 3
ER -