Figure 2. Key Figure: Ca²⁺ transport in cells.

The cartoon shows various sources and sinks for Ca²⁺ in cells. In going forward, these need to be considered carefully in studies of astrocytes. Changes in cytosolic Ca²⁺ are dynamically regulated through interplay between Ca²⁺ channels, pumps and transporters. A variety of Ca²⁺ channels exist which are expressed on both the plasma membrane and the membrane of organelles. Voltage-gated Ca²⁺ channels are highly selective plasma membrane proteins that mediate Ca²⁺ signals in excitable cells in response to membrane depolarization. A number of neurotransmitters mediate Ca²⁺ signals through less-selective ligand-gated ion channels. These include cell surface P2X receptors activated by ATP and the NMDA class of ionotropic receptors for glutamate (NMDAR). Nicotinic acetylcholine (AChR) and 5-HT3 (5HT3R) receptors are Ca²⁺-permeable members of the cys-loop family of ligand-gated ion channels activated by acetylcholine and 5-HT, respectively. TRP channels constitute a large family of widely expressed ion channels. They are divided into 6 families in mammals. Their Ca²⁺ selectivity varies widely and they are activated by a number of intracellular and extracellular cues including heat (e.g. TRPV1), cold (e.g. TRPM8), pungent chemicals (TRPA) and Ca²⁺ itself (TRPP2). TRPC channels are activated upon receptor-mediated signaling downstream of phospholipase C signaling via diacylglycerol in some cases. Orai channels are highly Ca²⁺-selective channels activated by the ER Ca²⁺ sensor STIM upon depletion of ER Ca²⁺ stores. Plasma membrane Ca²⁺ ATPase (PMCA) pumps and sodium-calcium exchangers (NCX) transport Ca²⁺ out of the cytosol. IP₃ receptors are intracellular Ca²⁺-permeable channels localized predominately to the ER where they mediate Ca²⁺ signals in response to IP₃ produced upon phospholipase C activation, which occurs downstream of GPCR activation. Receptor stimulation also elevates levels of, cyclic ADP-ribose (cADPR) which activates the related ryanodine receptors (RyR). The ER Ca²⁺ stores are filled by sarco-endoplasmic reticulum Ca²⁺ ATPases (SERCA The Golgi complex (not shown) also acts as a dynamic Ca²⁺ store housing IP₃ and ryanodine receptors for Ca²⁺ release and secretory pathway ATPases (together with SERCA) for filling. In addition to the ER, a number of acidic organelles which include lysosomes also serve as Ca²⁺ stores. These acidic Ca²⁺ stores express two-pore channels (TPCs), activated by the intracellular messenger NAADP, and TRPM2 activated by ADP-ribose (which additionally activates plasma membrane TRPM2). TRP mucolipins (TRPML) and P2X4 receptors are also expressed on lysosomes. Ca²⁺ is also dynamically regulated by mitochondria. Ca²⁺ is rapidly taken up by the mitochondrial uniporter (MCU) which is a Ca²⁺-permeable channel localized to the inner mitochondrial membrane. Ca²⁺ is slowly released back into the cytosol by the actions of a mitochondrially targeted sodium-calcium changer (NCLX). The Ca²⁺ concentrations for the intracellular compartments were taken from published work [58-60].