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. 2022 Sep 14;149(17):dev198853. doi: 10.1242/dev.198853

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© 2022. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Fig. 1. — Overview of intracellular calcium signaling. Schematic highlighting ion channels and pumps mediating cytoplasmic calcium homeostasis and select calcium-dependent pathways that transduce calcium signals to the nucleus. Low resting cytosolic calcium levels are maintained by plasma membrane calcium ATPases (PMCA1-4, encoded by ATP2B1-4), which extrude calcium out of the cell and display low calcium efflux capacity but high calcium affinity, and pumps on the surface of the sarco/endoplasmic reticulum (SR/ER) and mitochondria (e.g., the SR/ER calcium ATPases SERCA1-3, encoded by ATP2A1-3), which transport calcium into intraorganellar stores. Large calcium elevations are countered by sodium calcium exchangers (NCX1-4, encoded by SLC8A1-4) on the plasma membrane and mitochondrial and ER membranes. Calcium-permeable channels mediating calcium influx from the extracellular space include voltage-gated calcium channels (VGCCs), N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), transient receptor potential (TRP) channels and ORAI channels. VGCCs are activated by membrane depolarization, whereas ORAI channels allow calcium influx upon ER calcium store depletion. Successive release of calcium from the ER, mediated by IP3R or RyR, depletes ER calcium, which in turn activates STIM calcium sensors (STIM1 and STIM2) to promote their interaction with ORAI channels (ORAI 1-3) and subsequent calcium influx. Gap junctions in the plasma membrane allow for intercellular propagation of calcium signals, through direct transfer of ions or small molecules that are crucial for intracellular signaling (e.g. IP3). Calcium-sensitive proteins in the cytoplasm (e.g. calmodulin; CaM) undergo a conformational change upon calcium binding, initiating distinct signaling cascades to the nucleus that culminate in calcium-dependent transcription. Note that only select calcium-dependent transcription factors with reported roles in the developing nervous system are highlighted; other factors and organellar calcium stores (e.g. mitochondria, lysosomes, Golgi apparatus) are not depicted.