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Vol. 13, Issue 12, 4266-4278, December 2002

Role of Secretory Carrier Membrane Protein SCAMP2 in Granule Exocytosis

Lixia Liu, Zhenheng Guo,^* Quyen Tieu, Anna Castle, and David Castle

Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0001

In secretory carrier membrane proteins (SCAMPs), the most conserved structural segment is between transmembrane spans 2 and 3, facing the cytosol. A synthetic peptide, CWYRPIYKAFR (E peptide), from this segment of SCAMP2 potently inhibits exocytosis in permeabilized neuroendocrine (PC12) cells. E peptide blocked discharge of ³⁵S-labeled secretogranin with the same structural selectivity and potency as observed for hexosaminidase secretion in mast cells. SCAMPs 1 and 2 are concentrated primarily on intracellular membranes in PC12 cells. Both, however, are found on plasma membranes, but neither is present on large dense-core vesicles. Yet, large dense-core vesicles marked by secretogranin attach to plasma membranes at foci containing SCAMP2 along with syntaxin1 and complexin at putative cell-surface docking/fusion sites. Regulated overexpression of SCAMP2 with point mutations in its E peptide but not of normal SCAMP2 caused dose-dependent inhibition of depolarization-induced secretion. The SCAMP2 mutants also inhibited secretion stimulated by elevated calcium. Inhibition was largely overcome by adding lysophosphatidylcholine to the medium at concentrations that do not otherwise affect secretion. Although overexpression of normal or mutant SCAMP2 slightly inhibits endocytosis, this effect does not appear to be related to the specific effect of the mutant SCAMP on stimulated exocytosis. Thus, SCAMP2 not only colocalizes with fusion sites but also appears to have an essential function in granule exocytosis through actions mediated by its E peptide-containing domain.

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^* Present address: Department of Physiology, University of Kentucky Medical Center, Lexington, KY.

Corresponding author. E-mail address: jdc4r{at}virginia.edu.

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Molecular Biology of the Cell
Vol. 13, 4266-4278, December 2002
Copyright © 2002 by The American Society for Cell Biology

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