Research ArticlePhysiology

SOCE mediated by STIM and Orai is essential for pacemaker activity in the interstitial cells of Cajal in the gastrointestinal tract

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Sci. Signal.  12 Jun 2018:
Vol. 11, Issue 534, eaaq0918
DOI: 10.1126/scisignal.aaq0918

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Keeping the gut moving

The gut contracts periodically to mix and propel its contents. These rhythmic contractions are driven by the pacemaker activity of the interstitial cells of Cajal in the gut, which generate electrical slow waves that require Ca2+ release from the endoplasmic reticulum (ER). Zheng et al. showed that ER Ca2+ stores in the interstitial cells of Cajal were refilled by store-operated Ca2+ entry (SOCE), a process that was mediated by Orai Ca2+ channels and the STIM family of Ca2+ sensors. Some gastrointestinal motility disorders have been linked to defects in the activity of the interstitial cells of Cajal, which may be due to dysfunctional SOCE.

Abstract

Electrical pacemaker activity generates phasic contractions and motility patterns such as segmentation and peristalsis in the gastrointestinal tract. Pacemaker currents are generated in interstitial cells of Cajal (ICC), which release Ca2+ from intracellular stores that stimulates Ca2+-activated Cl channels (CaCCs) in the plasma membrane. Thus, Ca2+ stores must be maintained to sustain pacemaker activity. Store-operated Ca2+ entry (SOCE) facilitates the refilling of Ca2+ stores by a mechanism dependent upon interactions between STIM and Orai proteins. We investigated the role of SOCE in ICC pacemaker activity. Reintroduction of extracellular Ca2+ in store-depleted ICC resulted in CaCC activation. Blocking CaCCs revealed an inwardly rectifying current with properties of a Ca2+ release–activated current (ICRAC). An inhibitory peptide that interfered with the STIM-Orai interaction blocked ICRAC in HEK 293 cells expressing STIM1 and Orai1 and blocked spontaneous transient inward currents (STICs) and slow wave currents in ICC. STICs, which are fundamental pacemaker events in ICC, were blocked by an Orai antagonist. Imaging of Ca2+ transients linked to pacemaker activity in ICC in intact muscles showed that the Orai antagonist blocked Ca2+ transients in ICC. These data suggest that Ca2+ recovery through STIM-Orai interactions is necessary to maintain ICC pacemaker activity.

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