Description:

Mohamed Trebak, Ph.D.
Professor
Department of Cellular and Molecular Physiology
Penn State Cancer Center

Abstract:
Ligation of phospholipase C (PLC)-coupled receptors causes downstream production of inositol(1,4,5)-trisphosphate (IP3), activation of IP3 receptors located in the endoplasmic reticulum (ER) and subsequent depletion of ER Ca2+ stores. ER Ca2+ depletion is sensed by stromal interacting molecules (STIM), which change conformation and move to ER-plasma membrane junctions to trap and activate Orai channels and induce Ca2+ entry from the extracellular space. This ubiquitous and evolutionarily conserved Ca2+ entry mechanism is termed store operated Ca2+ entry (SOCE) pathway and its biophysical manifestation is known as the Ca2+ release-activated Ca2+ (CRAC) current. SOCE is crucial for many physiological functions, including immune competence, exocrine secretion, muscle contraction, female lactation and male fertility. Both gain and loss of CRAC channel function is associated with disease. Invertebrates express one ER-resident Ca2+-sensing STIM and one Orai plasma membrane channel protein. The crucial role of their vertebrate homologues, STIM1 and Orai1 in mediating SOCE and CRAC activity in mammals is well-established. However, mammals possess two STIM and three Orai isoforms encoded by five independent genes. The involvement of all STIM/Orai proteins as well as the choreography of their interactions under physiological receptor activation are unknown. Here, we describe that the five native mammalian STIM1/2 and Orai1/2/3 isoforms have non-redundant functions and that they are always required together during receptor activation to ensure the graded diversity and fidelity of mammalian Ca2+ signaling in response to the full spectrum of agonist strengths. We show how the coordinated functions of all five STIM/Orai proteins at both the ER-lumen and cytosol translate the strength of agonist stimulation to precise levels of Ca2+ release, Ca2+ entry and nuclear factor of activated T-cells (NFAT) activation, ensuring the diversity and fidelity of complex mammalian Ca2+ signaling.