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Orai and Stim proteins are the mediators of calcium release-activated calcium signaling and are important in the regulation of bone homeostasis and disease. This includes separate regulatory systems controlling mesenchymal stem cell differentiation to form osteoblasts, which make bone, and differentiation and regulation of osteoclasts, which resorb bone. These systems will be described separately, and their integration and relation to other systems, including Orai and Stim in teeth, will be briefly discussed at the end of this review.

A paper by Gok et al., identified Zinc Finger DHHC-Type Palmitoyltransferase 5 (zDHHC5) and Acyl-Protein Transferase 1 (APT1) as the enzymes responsible for the dynamic palmitoylation of NCX1. Palmitoylation occurs at the cell surface and increases the affinity of NCX1 for lipid rafts. Additionally, they discovered that palmitoylation controls the affinity of NCX1 for exchange inhibitory protein (XIP) and regulates intracellular calcium concentration. These findings provide new insights into endogenous control of NCX1 function and will drive future investigations directed at understanding its full potential.

In a September 2018 paper published in Nature Communications, Gong et al. identified the domains through which human PMCA1 and neuroplastin (NPTN) interact. Upon binding, hPMCA1 TM domains separate T110 in TM1 and A370 in TM3 to reveal the Ca2+-binding site. Thus, NPTN is able to directly modulate the accessibility of cytosolic Ca2+ to PMCA.

Ca(2+) is a dynamic cellular secondary messenger which mediates a vast array of cellular responses. Control over these processes is achieved via an extensive combination of pumps and channels which regulate the concentration of Ca(2+) within not only the cytosol but also all intracellular compartments. Precisely how these pumps and channels are regulated is only partially understood, however, recent investigations have identified members of the Early Growth Response (EGR) family of zinc finger transcription factors as critical players in this process. The roles of several other transcription factors in control of Ca(2+) homeostasis have also been demonstrated, including Wilms Tumor Suppressor 1 (WT1), Nuclear Factor of Activated T cells (NFAT) and c-myc. In this review, we will discuss not only how these transcription factors regulate the expression of the major proteins involved in control of Ca(2+) homeostasis, but also how this transcriptional remodeling of Ca(2+) homeostasis affects Ca(2+) dynamics and cellular responses.

Ca(2+) signals are universal among cells in regulating a spectrum of cellular responses. Phospholipase C-coupled receptors activate two components of Ca(2+) signals--rapid Ca(2+) release from ER stores, followed by slower Ca(2+) entry from outside the cell. The coupling process between ER and PM to mediate this "store-operated" Ca(2+) entry process remained until recently a molecular mystery. The recent discovery of the necessity for STIM1 and Orai proteins in this process has provided crucial information on the coupling mechanism between stores and PM Ca(2+) entry. STIM1 is a single spanning membrane protein with an unpaired Ca(2+) binding EF-hand and appears to function as the sensor of ER luminal Ca(2+), and, through redistribution in the ER, transduces information directly to the PM. Orai1 is a tetra-spanning PM protein and functions as the highly Ca(2+)-selective channel in the PM that is gated through interactions with the store-activated ER Ca(2+) sensor. Recent evidence shows the two proteins together are necessary and sufficient for the function of store-operated Ca(2+) entry. However, many questions arise about how and where the interactions of the STIM1 and Orai1 proteins occur within cells. Here we discuss recent information and ideas about the coupling between these proteins that leads to store-operated channel activation.