Calcium-Calcineurin Signaling in S. cerevisiae
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Calcium-Calcineurin Signaling in S. cerevisiae

Cells of S. cerevisiae (Saccharomyces cerevisiae) produce one of two Mating pheromones, A-Factor and MF-Alpha (Mating Factor-Alpha). Mating pheromones bind to their receptors like Ste2 (Sterile/Alpha-Factor Pheromone Receptor) and Ste3 (Pheromone A-Factor Receptor), which leads to G-protein activation and induces the dissociation of the heterotrimeric G-protein subunits designated Gpa1 (Alpha-Subunit), Ste4 (Beta-Subunit), and Ste18 (Gamma-Subunit). These pheromones prepare cells for mating by inducing cell cycle arrest in G1 and also raises the levels of intracellular Ca2+ (Calcium) and induce activation of Calcineurin Complex (or Calcium-Dependent Protein Serine/Threonine Phosphatase Complex). The S. cerevisiae Calcineurin Complex consists of four proteins: Two Calcineurin-A subunits, CNA1 (Calcineurin Subunit-A/Type-2B protein Serine/Threonine Phosphatase Catalytic Subunit-A1) and CNA2 (Calcineurin Subunit-A/Type-2B Protein Serine/Threonine Phosphatase); a Calcineurin Regulatory B-subunit known as CNB1 (Calcineurin Regulatory B-Subunit Type-2B Protein Phosphatase) and RCN1 (Regulator of Calcineurin/Calcineurin Inhibitor) which acts an inhibitor. Calcineurin is involved in the regulation of Ca2+ pumps and exchangers responsible for Ca2+ homeostasis in yeast (Ref.1). It maintains cytoplasmic Ca2+ balance. One of the downstream signaling components regulated by Calcineurin is the transcription factor CRZ1 (Calcineurin-Responsive Zinc Finger). CRZ1 is required for Calcineurin-dependent induction of genes for the vacuolar and secretory Ca2+ pumps, Pmc1 (Putative Vacuolar Ca2+ ATPase) and Pmr1 (High affinity Ca2+/Mn2+ (Manganese) P-type ATPase); one of two genes encoding Fks2/GSC2 (Glucan Synthase of Cerevisiae/1,3-Beta-D-Glucan Synthase Catalytic Component); and the gene for the plasma membrane Na+ pump, Pmr2 (P-Type ATPase Sodium Pump). Calcineurin also regulate the high/low-affinity state of the plasma membrane K+ (Potassium) channel, Trk1 (180 kDa High Affinity Potassium Transporter), Trk2 (Low Affinity Potassium Transport Membrane Protein), Hal1 (Halotolerance/Polar 32-kDa Cytoplasmic Protein) and inhibit VCX1 (Vacuolar H+ (Hydrogen)/Ca2+ Exchanger) by post-tranlational mechanisms. Ca2+ dependent transcription is blocked by the immunosuppressive drugs CsA (Cyclosporin-A) and FK506 (Tacrolimus) that act as potent inhibitors of Calcineurin (Ref.2).

The role of Calcineurin in Na+ (Sodium)/Li+ (Lithium) tolerance is mediated by transcriptional and post translational mechanisms. Adaptation to high salt stress requires the presence of a plasma membrane Na+-ATPase involved in Na+ and Li+ efflux, Pmr2. Ca2+, via Cmd1 (Calmodulin) activation of Calcineurin, regulates adaptation to high salt stress by induced expression of Pmr2, mediated by CRZ1. This provides both transcriptional and post-translational regulation of Na+ efflux mediated by Ca2+. The K+ transport system (Trk1 and Trk2) is converted to a high-affinity state by CNB1 (Calcineurin Regulatory B-Subunit Type-2B Protein Phosphatase). In the high-affinity state, this pump has increased affinity for K+; however Na+ or Li+ efflux remains unaffected, thereby resulting in increased Na+ uptake in yeast cells. The mechanism of this regulation depends on direct or indirect dephosphorylation of Trk by Calcineurin. In addition, other ion transporters indirectly influence intracellular Ca2+. One of these is VCX1. Two Ca2+-ATPases, Pmc1 and Pmr1, are responsible for depleting the cytosolic Ca2+ (Ref.2). Pmc1 is localized to the vacuole, while Pmr1 is important in the secretory pathway and localizes to the Golgi. Activation of Calcineurin leads to transcriptional induction of the Pmc1 and Pmr1 genes via CRZ1. Pmr1, the Golgi-localized Ca2+ pump, plays an important role in Mn2+ tolerance by sequestering Mn2+ to late compartments in the secretory pathway. Mn2+ is transported into the vacuole via VCX1. Calcineurin is also responsible for transcriptional regulation of Fks2/GSC2. The Fks2 protein is induced upon Mating Pheromone action, high Ca2+, or growth on poor carbon sources. Hence, Calcineurin plays a vital role in regulating cell wall structure also. High Ca2+ influx is mediated through Calcium channel protein CCH1 (Calcium Channel (Putative)) and Mid1 (N-Glycosylated Integral Plasmamembrane Protein), apart from these environmental factors like Temperature Stress also mediate Ca2+ entry (Ref.3).

Pmr2 expression is regulated by Std1 (Protein that interacts with the SNF1 (Sucrose Non-Fermenting/Protein Serine/Threonine Kinase) and SPT15 (Suppressor of Ty) and Calcineurin. Cellular response to Na+ ion stress occurs in two parallel pathways. Both pathways converge in the nucleus where transcriptional induction of genes such as Hal1, Pmr2 and Fks2/GSC2 occur. Cation homeostasis is regulated by both Cmd1 and Calcineurin acting on the Pmr2 and Trk, respectively (Ref.1). SNF3 (Sucrose Non-Fermenting/Glucose Sensor) and Rtg2 (Retrograde Regulation Protein-2) function as negative regulators of Na+ stress response and their loss of function serves to increase the expression of  Na+ ion stress response genes. SNF3 and Rtg2 basically act as Glucose sensors. Loss of Glucose sensors cause derepression of the Na+ stress response genes that are under Glucose control and thereby enhances the Na+ stress response of the cells. Transcriptional response to Na+ ion stress is involved in chromatin remodeling, since yeast cells lacking functional activity of Swi/SNF (Sucrose Non-Fermenting) Complex have a greatly reduced tolerance to Na+ ion stress. Since Calcineurin is essential in CsA- and FK506-sensitive yeast strains, the possibility that novel Calcineurin inhibitors might be developed as specific antifungal and antiparasitic agents cannot be ruled out. It is plausible that the physiological roles of Calcineurin are similar in human and yeast cells. Thus there is a need to identify the downstream targets and functions of yeast Calcineurin as a framework for understanding Ca2+-signaling mechanisms and responses in human cells (Ref.2 & 3).