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E-Conference: Defining Calcium Entry Signals

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Store-operated Calcium Entry- Contiguous ER or ER resident proteins?

1 June 2004

Randen L. Patterson

A role for the contiguous ER in the activation of store-operated calcium (SOC) entry at a glance would seem undeniable, although molecular evidence defending this hypothesis is minimal. In general, SOC is activated by the application of:

1) pathophysiological plant defense toxins (thapsigargin) that inhibit SERCA, thus passively depleting calcium storage pools, or

2) application of ionophores to release calcium from internal membrane compartments.

Either of these strategies would deplete any calcium pool that was actively maintained; therefore these studies do not provide conclusive evidence for the role of the contiguous ER in SOC.

Both of these methodologies have been examined using knock-down or knock- out strategies to define molecular constituents of SOC, in particular the IP3-receptor and SERCA. A “minimal at best” alteration of SOC has been observed under these conditions, ruling out a requirement for these proteins in the activation or maintenance mechanisms of store-operated calcium entry.

The strongest data supporting a role of the contiguous ER in SOC comes from two recent studies looking at the sarcoplasmic reticulum, not the ER, in skeletal muscle. These studies demonstrate a functional link between the calcium storage protein calsequestrin and the synaptophysin-family-related protein Mitsugumin 29 (located in the junction between the PM and SR of skeletal muscle), with both influencing store-operated calcium entry. Unfortunately, other studies looking at reduction of calreticulin in hepatocytes did not support this hypothesis. Taken together, although pathophysiological depletion of internal calcium stores absolutely activates SOC, the calcium pool(s) responsible has not been defined.

Twenty years of studying the effects of thapsigargin and iononphores to elicit SOC has not provided any concrete evidence as to the molecular entities in the ER, or anywhere for that matter, responsible for this phenomenon. More rigorous molecular approaches (gene-chip of ER depleted cells vs. control, sequential siRNA deletion of calcium related ER proteins, real-time chromophore inactivation of ER resident proteins etc.) using physiological methods for depleting calcium pools (chronic agonist stimulation) are likely to provide molecular entities that can be identified, modified, and tested for a definitive role is SOC.

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882