Kinetics of internalization and degradation of N-type voltage-gated calcium channels: Role of the α2/δ subunit

Geula M. Bernstein, Owen T. Jones

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    The contribution of voltage-gated calcium channels to excitable cell function depends, critically, upon the mechanisms that control their expression at the cell surface. While co-assembly of the pore forming α1 and auxiliary β subunits enhances channel surface expression, the levels are still only 30-40% of those seen with the core α1B/β1b/α2δ calcium channel complex. To rationalize this observation, it has been suggested that the α2/δ subunit might stabilize calcium channel expression at the cell surface. To test this notion, we have resolved the effect of the α2/δ subunit on the rates of binding, internalization and degradation of defined N-type calcium channel surface complexes expressed in HEK293 cells, through pulse-labeling with the selective, cell impermeable, radioligand [125I]-ω-CgTx. Through detailed kinetic and sensitivity analysis we show that α1B/β1b/α2δ complexes are internalized slowly (kint 0.4/h), whereupon, most become degraded (kdeg 0.02/h). In contrast, α1B/β1b complexes are internalized more rapidly (kint 0.8/h), following which they are either quickly degraded (kdeg 0.1/h) or are sequestered slowly (ktra 0.1/h) to a pool that is metabolically stable within the time-frame of our experiments (24 h). In neither case did we find evidence for recycling via the cell surface. Thus, our data argue for a novel mechanism where complexes lacking an α2/δ subunit are cleared from the cell surface and are rapidly degraded or stored, possibly for further attempts at complexation as new α2/δ subunits become available. The slower rate of internalization of complexes containing the α2/δ subunit rationalizes the stabilizing effect this subunit has upon calcium channel surface expression and suggests a mechanism by which α2δ mutations may cause severe neurological deficits. © 2006 Elsevier Ltd. All rights reserved.
    Original languageEnglish
    Pages (from-to)27-40
    Number of pages13
    JournalCell calcium
    Issue number1
    Publication statusPublished - Jan 2007


    • Conotoxin
    • Endocytosis
    • Internalization
    • N-type calcium channel
    • Subunit


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