Structural and functional aspects of calcium homeostasis in eukaryotic cells

Abstract

The maintenance of a low cytosolic free-Ca2+ concentration, ([Ca2+Ii) is a common feature of all eukaryotic cells. For this purpose a variety of mechanisms have developed during evolution to ensure the buffering of Ca2+ in the cytoplasm, its extrusion from the cell and/or its accumulation within organelles. Opening of plasma membrane channels or release of Ca2+ from intracellular pools leads to elevation of [Ca2+Ii; as a result, Ca2+ binds to cytosolic proteins which translate the changes in [Ca2+Ii into activation of a number of key cellular functions.The purpose of this review is to provide a comprehensive description of the structural and functional characteristics of the various components of [CaZ+li homeostasis in eukaryotes.It is well known how Sidney Ringer recognized the role of Ca2+ in muscle contraction [l] and how fortunate it was that he was working with frog heart muscle, rather than with skeletal muscle, given that contractility in the latter muscle is basically independent of extracellular Ca2 + . Less appreciated is the fact that it took a century before a wide-range test of the 'Ca2+ hypothesis' in the mediation of cellular responses became possible. So many years in fact elapsed between the publication of the seminal paper by Ringer in 1883 [l] and the report in 1982 by Tsien and co-workers [2] describing the application of quin 2 to the measurement of intracellular free Ca2+ ([Ca2++Ii) in small mammalian cells.The exploitation of fluorescent tetracarboxylate/pentacarboxylate dyes for measuring Ca2 + has enabled a thorough testing of Ca2+ involvement in a host of cellular responses spanning fertilization to muscle contraction, proliferation to neurotransmitter release and cell motility to cell death. The fluorescent dye technique has also complemented biochemistry, electrophysiology and molecular biology, and allowed the description in real time of the actual changes in [Ca2+Ii following the activation of membrane Ca2+ influx/ efflux pathways. Additional levels of complexity have emerged from the application of these techniques to the study of C a 2 + homeostasis and new problems have arisen, yet for the first Correspondewe to T. Pozzan, Institute of General Pathology, University of Ferrara, Via Borsari 46, 1-35121 Ferrara, ItalyAbbreviations. [Ca' +Ii, cytosolic free-Caz + concentration; VOC, voltage-operated channel; ROC, receptor-operated channel ; SMOC, second messenger-operated channcl; GOC, G-protein-operated channel; EC coupling, excitation-contraction coupling; MeDAsp, N-methyl u-aspartate; Ins(1 ,4,5)P3, inositol 1,4,5-trisphosphatc; Ins(1,3,4,5)P4, inositol 1,3,4,5-tetrakisphosphate; PtdIns(4,5)P2, phosphatidylinositol(4,5) bisphosphatc; SR, sarcoplasmic reticulum; ER. endoplasmic reticulum; TC, terminal cisternae; El. enzyme form 1 of ATPase; E2, enzyme form 2 of ATPase; G-protein, guanylnucleotide-binding protein.time we are beginning to understand CaZi signaling as the integration of multiple pathways.Ca" is maintained in the cytoplasm of mammalian cells at a concentration tha...

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