期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 32, 页码 11230-11235出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0504183102
关键词
integrin; neuron; motif; expression
资金
- Wellcome Trust Funding Source: Medline
All auxiliary alpha 2 delta subunits of voltage-gated Ca2+ (Cav) channels contain an extracellular Von Willebrand factor-A (VWA) domain that, in alpha(2)delta-1 and -2, has a perfect metal-ion-dependent adhesion site (MIDAS). Modeling of the a(2)delta-2 VWA domain shows it to be highly likely to bind a divalent cation. Mutating the three key MIDAS residues responsible for divalent cation binding resulted in a MIDAS mutant alpha(2)delta-2 subunit that was still processed and trafficked normally when it was expressed alone. However, unlike WT alpha(2)delta-2, the MIDAS mutant a(2)delta-2 subunit did not enhance and, in some cases, further diminished Cav1.2, -2.1, and -2.2 currents coexpressed with beta 1b by using either Ba2+ or Na+ as a permeant ion. Furthermore, expression of the MIDAS mutant alpha(2)delta-2 reduced surface expression and strongly increased the perinuclear retention of Caval subunits at the earliest time at which expression was observed in both Cos-7 and NG108-15 cells. Despite the presence of endogenous alpha(2)delta subunits, heterologous expression of alpha(2)delta-2 in differentiated NG108-15 cells further enhanced the endogenous high-threshold Ca2+ currents, whereas this enhancement was prevented by the MIDAS mutations. Our results indicate that alpha(2)delta subunits normally interact with the Caval subunit early in their maturation, before the appearance of functional plasma membrane channels, and an intact MIDAS motif in the alpha(2)delta subunit is required to promote trafficking of the alpha 1 subunit to the plasma membrane by an integrin-like switch. This finding provides evidence for a primary role of a VWA domain in intracellular trafficking of a multimeric complex, in contrast to the more usual roles in binding extracellular ligands in other exofacial VWA domains.
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