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J. Biol. Chem., Vol. 277, Issue 8, 6359-6365, February 22, 2002

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Genetic Analysis of -Latrotoxin Receptors Reveals Functional Interdependence of CIRL/Latrophilin 1 and Neurexin 1^*

Sönke Tobaben, Thomas C. Südhof^§, and Bernd Stahl^¶

From the  Max-Planck-Institute for Experimental Medicine, 37075 Göttingen, Germany and the ^§ Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111

-Latrotoxin triggers massive neurotransmitter release from nerve terminals by binding to at least two distinct presynaptic receptors, neurexin 1 and CIRL1/latrophilin1 (CL1). We have now generated knockout (KO) mice that lack CL1 and analyzed them alone or in combination with neurexin 1 KO mice. Mice lacking only CL1, or both CL1 and neurexin 1, were viable and fertile. Ca²⁺-independent binding of -latrotoxin to brain membranes was impaired similarly in CL1 single and in CL1/neurexin 1 double KO mice (~75% decrease) but not in neurexin 1 single KO mice. In contrast, Ca²⁺-dependent binding (~2 times above Ca²⁺-independent binding) was altered in both CL1 (~50% decrease) and neurexin 1 single KO mice (~25% decrease) and was decreased further in double KO mice (~75% decrease). Synaptosomes lacking CL1 exhibited the same decrease in -latrotoxin-stimulated glutamate release in the presence and absence of Ca²⁺ (~75%). In contrast, synaptosomes lacking neurexin 1 exhibited only a small decrease in -latrotoxin-triggered release in the absence of Ca²⁺ (~20%) but a major decrease in the presence of Ca²⁺ (~75%). Surprisingly, synaptosomes lacking both CL1 and neurexin 1 displayed a relatively smaller decrease in -latrotoxin-stimulated glutamate release than synaptosomes lacking only CL1 in the absence of Ca²⁺ (~50 versus ~75%), but the same decrease in the presence of Ca²⁺ (~75%). Our data suggest the following two major conclusions. 1) CL1 and neurexin 1 together account for the majority (75%) of -latrotoxin receptors in brain, with the remaining receptor activity possibly due to other CL and neurexin isoforms, and 2) the two receptors act additively in binding -latrotoxin but not in triggering release. Together these data suggest that the two receptors act autonomously in binding of -latrotoxin but cooperatively in transducing the stimulation of neurotransmitter release by -latrotoxin.

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