Figure 2.

Classical view of the major players in the system that regulates intracellular Ca²⁺ compartmentalization. Cellular Ca²⁺ import through the plasma membrane occurs largely by receptor-operated (for example, glutamate receptors), voltage-sensitive and store-operated channels. Once inside the cell, Ca²⁺ can either interact with Ca²⁺-binding proteins or become sequestered into the endoplasmic reticulum (ER) or mitochondria. The largest Ca²⁺ store in cells is found in the ER or sarcoplasmic reticulum, with local Ca²⁺ concentrations reaching millimolar levels. Ca²⁺ levels in the ER are affected by the relative distribution of sarco(endo)plasmatic reticulum Ca²⁺-ATPase (SERCA) pumps and of inositol-1, 4, 5-triphosphate (Ins(1, 4, 5)P₃) receptors (Ins(1, 4, 5)P₃Rs) and ryanodine receptors (RYRs), as well as by the relative abundance of Ca²⁺-binding proteins (calreticulin, calsequestrin) in the ER or sarcoplasmic reticulum. The cytosolic Ca²⁺ concentration in unstimulated cells is kept at approximately 100 nM by both uptake into the ER and Ca²⁺ extrusion into the extracellular space by the plasma-membrane Ca²⁺-ATPase (PMCA). ER Ca²⁺ release is triggered by agonist stimulation through the generation of Ins(1, 4, 5)P₃ through hydrolysis of phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P₂) operated by a phospholipase C (PLCγ). The mitochondria take up Ca²⁺ electrophoretically through a uniport transporter and can release it again through 3 different pathways: reversal of the uniporter, Na⁺/H⁺-dependent Ca²⁺ exchange, or as a consequence of permeability transition pore (PTP) opening. The PTP can also flicker to release small amounts of Ca²⁺. Ca²⁺ efflux from cells is regulated primarily by the PMCA, which binds calmodulin and has a high affinity for Ca²⁺. Ca²⁺ efflux might also be mediated by the Na⁺/Ca²⁺ exchanger (NCX). [Ca²⁺], calcium concentration; DAG, diacylglyceride. This figure was kindly provided by Prof. S. Orrenius. It served as the template for a figure in: Orrenius, S., Zhivotovsky, B., Nicotera, P. (2003). Nature Reviews of Cell Biology 4, 552–556.¹⁸ The figure was slightly modified by adding the red dots with FLS, suggesting a role for endogenous sesquiterpenoids (FLS) as agonists for Ca²⁺-ATPases. Such role is more probable for SERCAs than for PMCAs (hence the question mark).With copyright permission for both the figure and the legend from the publisher and from Prof. S. Orrenius.