Emergence of broad cytosolic Ca2+ oscillations in the absence of CRAC channels: A model for CRAC-mediated negative feedback on PLC and Ca2+ oscillations through PKC

Lloyd Lee

University of Auckland

"Emergence of broad cytosolic Ca2+ oscillations in the absence of CRAC channels: A model for CRAC-mediated negative feedback on PLC and Ca2+ oscillations through PKC"

The role of Ca2+ release-activated Ca2+ (CRAC) channels mediated by ORAI isoforms in calcium signalling has been extensively investigated. It has been shown that the presence or absence of different isoforms has a significant effect on Store Operated Calcium Entry (SOCE). Yoast et al. [Nature Communications, 11(1), 2444 (2020)] have shown that, in addition to the reported narrow-spike oscillations (whereby cytosolic calcium decreases quickly after a sharp increase), ORAI1 knockout HEK293 cells were able to oscillate with broad-spike oscillations (whereby cytosolic calcium decreases in a prolonged manner after a sharp increase) when stimulated with a muscarinic agonist. This suggests that Ca2+ influx through ORAI1-mediated CRAC channels negatively regulates the duration of Ca2+ oscillations. We hypothesize that, through the activation of protein kinase C (PKC), ORAI1 negatively regulates phospholipase C (PLC) activity to decrease IP3 production and limit the duration of agonist-evoked Ca2+ oscillations. Based on this hypothesis, we construct a new mathematical model, which shows that the formation of broad-spike oscillations is highly dependent on the absence of ORAI1. Predictions of this model are consistent with the experimental results.
Additional authors: Ryan Yoast; Scott Emrich; Mohamed Trebak; Vivien Kirk; James Sneyd

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