A STIM1-dependent 'trafficking trap' mechanism regulates Orai1 plasma membrane residence and Ca²⁺ influx levels. Academic Article uri icon

Overview

abstract

  • The key proteins mediating store-operated Ca(2+) entry (SOCE) are the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 and the plasma membrane Ca(2+)-selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (Kex≃0.1 min(-1)), with ∼40% of the total Orai1 pool localizing to the plasma membrane at steady state. A subset of intracellular Orai1 localizes to a sub-plasmalemal compartment. Store depletion is coupled to Orai1 plasma membrane enrichment in a STIM1-dependent fashion. This is due to trapping of Orai1 into cortical ER STIM1 clusters, leading to its removal from the recycling pool and enrichment at the plasma membrane. Interestingly, upon high STIM1 expression, Orai1 is trapped into STIM1 clusters intracellularly, thus preventing its plasma membrane enrichment following store depletion. Consistent with this, STIM1 knockdown prevents trapping of excess Orai1 into limiting STIM1 clusters in the cortical ER. SOCE-dependent Ca(2+) influx shows a similar biphasic dependence on the Orai1:STIM1 ratio. Therefore, a STIM1-dependent Orai1 'trafficking trap' mechanism controls Orai1 plasma membrane enrichment and SOCE levels, thus modulating the SOCE 'bandwidth' for downstream signaling.

publication date

  • June 26, 2015

Research

keywords

  • Calcium
  • Calcium Channels
  • Calcium Signaling
  • Membrane Proteins
  • Neoplasm Proteins

Identity

Scopus Document Identifier

  • 84939507264

Digital Object Identifier (DOI)

  • 10.1242/jcs.172320

PubMed ID

  • 26116575

Additional Document Info

volume

  • 128

issue

  • 16