Regulation of Orai/STIM Channels by pH

Review
In: Calcium Entry Channels in Non-Excitable Cells. Boca Raton (FL): CRC Press/Taylor & Francis; 2018. Chapter 9.

Excerpt

Ca2+ signaling is crucial in a variety of physiological/pathological processes associated with acidosis and alkalosis. In particular, capacitive Ca2+ entry [1] through the Ca2+ release-activated Ca2+ (CRAC) channels [2] plays an essential role in mediating intracellular and extracellular acidification and alkalinization-induced functional changes. Physiologically, intracellular alkalinization is associated with various physiological functions such as activity-dependent membrane depolarization [3], oocyte maturation [4], oocyte fertilization, sperm activation [5–7], mast cell degranulation [8], smooth muscle contraction [9], and growth factor-induced cell proliferation, differentiation, migration, and chemotaxis [10] (Figure 9.1). Pathologically, intracellular alkalinization is a hallmark of malignant cells associated with tumor progression [11,12], whereas acidic intracellular pH (pHi) has been shown to promote apoptosis [13]. Additionally, extracellular acidosis is another hallmark of tumor progression [11,12], and also a major cause of immunodeficiency in clinical acidosis due to impaired lymphocyte proliferation and cytotoxicity [14]. Furthermore, extracellular low pH, which occurs under injury and ischemic conditions, inhibits a number of cellular responses, including cytosolic- and membrane-associated enzyme activities as well as ion transport and ion channel activities [14].

Like many other ion channels, native ICRAC is inhibited by acidic but potentiated by basic extracellular or intracellular solutions in various cell types including macrophages [15], Jurkat T-lymphocytes [16], SH-SY5Y neuroblastoma cells [17], and smooth muscle cells [18]. Moreover, it has been shown that intracellular alkalinization-induced increase in intracellular Ca2+ is essential for platelet aggregation in response to thrombin [19]. Similarly, extracellular acidosis-induced inhibition, as well as alkalosis-induced stimulation of platelet aggregation, is mediated by changes in store-operated Ca2+ entry [20]. Furthermore, store-operated Ca2+ entry was suggested to mediate intracellular alkalinization in neutrophils [21], and a variety of growth factors have been demonstrated to induce cytosolic alkalinization together with Ca2+ entry [8]. Given the essential role of ICRAC in acidosis- and alkalosis-associated physiological and pathological processes, there is a great interest in understanding the molecular basis of CRAC channel regulation by intracellular and extracellular pH.

The discovery of the molecular basis of ICRAC and its gating mechanisms [22–29] provides a great opportunity to investigate the molecular basis of pH regulation of ICRAC. CRAC channel activity can be influenced by alterations of either the coupling of Orai and STIM subunits or biophysical properties of the pore-forming Orai subunit. Thus, pH regulation of ICRAC can be mediated by influencing this coupling process and/or by changing the biophysical characteristics of the pore-forming Orai subunits. Using Ca2+ imaging techniques, a previous study suggested that cytosolic alkalinization may lead to store depletion and therefore activate Orai1/STIM1 channels [30], whereas several other studies demonstrated that cytosolic alkalinization-induced Ca2+ release is not always related to Ca2+ entry [31–33]. Moreover, intracellular low pH caused by oxidative stress may result in uncoupling of Orai1 and STIM1, thereby inhibiting CRAC currents [34]. Recent studies have focused on using heterologously expressed Orai/STIM channels to fully understand how these channels are regulated by high and low internal and external pH, as well as the molecular basis of pH regulation of Orai/STIM [35–37].

This chapter summarizes recent advances in our understanding of pH regulation of ICRAC by focusing on how Orai/STIM channels are regulated by pH and the potential molecular basis of pH regulation. We summarize the essential methods required to investigate the influence of pH on Orai/STIM channel function as well as molecular mechanisms of pH regulation and highlight future directions in this exciting research field.

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  • Review