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Vol. 57, Issue 3, 519-528, March 2000
-Latrotoxin and Neurexin 1
Facilitate Toxin-Induced Channel Formation: Evidence That Channel
Formation Results from Tethering of Toxin to Membrane
Department of Pharmacology, University of Michigan Medical School,
Ann Arbor, Michigan (M.D.H., R.W.H.); Department of Physiology,
University of Michigan Medical School, Ann Arbor, Michigan (E.L.S.);
and the Departments of Pharmacology and Physiology and Neuroscience,
New York University Medical Center, New York, New York (V.G.K., A.G.P.)
-Latrotoxin binding to the calcium-independent receptor for
-latrotoxin (CIRL-1), a putative G-protein-coupled receptor, stimulates secretion from chromaffin and PC12 cells. Using patch clamp
techniques and microspectrofluorimetry, we demonstrate that the
interaction of -latrotoxin with CIRL-1 produces a high conductance channel that permits increases in cytosolic Ca2+.
-Latrotoxin interaction with CIRL-1 transiently expressed in bovine
chromaffin cells produced a 400-pS channel, which rarely closed under
Ca2+-free conditions. The major effect of overexpressing
CIRL-1 was to greatly increase the sensitivity of chromaffin cells to
channel formation by -latrotoxin. -Latrotoxin interaction with
CIRL-1 transiently overexpressed in non-neuronal human embryonic kidney 293 (HEK293) cells produced channels that were nearly identical with
those observed in chromaffin cells. Channel currents were reduced by
millimolar Ca2+. At -latrotoxin concentrations below 500 pM, channel formation occurred many seconds after binding of toxin to
CIRL-1 indicating distinct steps in channel formation. In all cases
there was a rapid, sequential addition of channels once the first
channel appeared. An analysis of CIRL-1 mutants indicated that channel formation in HEK293 cells is unlikely to be transduced by a
G-protein-dependent mechanism. -Latrotoxin interaction with a fusion
construct composed of the extracellular domain of CIRL-1 anchored to
the membrane by the transmembrane domain of vesicular stomatitis virus
glycoprotein, and with neurexin 1, an -latrotoxin receptor
structurally unrelated to CIRL-1, produced channels virtually identical
with those observed with wild-type CIRL-1. We propose that
-latrotoxin receptors recruit toxin to facilitate its insertion
across the membrane and that -latrotoxin itself controls the
conductance properties of the channels it produces.
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