Feedback modulation of Orai1α and Orai1β protein content mediated by STIM proteins

Store-operated Ca2+ entry is a mechanism controlled by the filling state of the intracellular Ca2+ stores, predominantly the endoplasmic reticulum (ER), where ER-resident proteins STIM1 and STIM2 orchestrate the activation of Orai channels in the plasma membrane, and Orai1 playing a predominant role. Two forms of Orai1, Orai1 alpha and Orai1 beta, have been identified, which arises the question whether they are equally regulated by STIM proteins. We demonstrate that STIM1 preferentially activates Orai1 alpha over STIM2, yet both STIM proteins similarly activate Orai1 beta. Under resting conditions, there is a pronounced association between STIM2 and Orai1 alpha. STIM1 and STIM2 are also shown to influence the protein levels of the Orai1 variants, independently of Ca2+ influx, via lysosomal degradation. Interestingly, Orai1 alpha and Orai1 beta appear to selectively regulate the protein level of STIM1, but not STIM2. These observations offer crucial insights into the regulatory dynamics between STIM proteins and Orai1 variants, enhancing our understanding of the intricate processes that fine-tune intracellular Ca2+ signaling.