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Calcium is a common signaling mechanism, as once it enters the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Calcium can act in signal transduction after influx resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.
Calcium signaling through ion channels
Movement of calcium ions from the extracellular compartment to the intracellular compartment alters membrane depolarisation. This is seen in the heart, during the plateau phase of ventricular contraction. In this example, calcium acts to maintain depolarisation of the heart.
Calcium as a secondary messenger
Important physiological roles for calcium signaling range widely. These include muscle contraction, neuronal transmission as in an excitatory synapse, cellular motility (including the movement of flagella and cilia), fertilisation, cell growth or proliferation, learning and memory as with synaptic plasticity, and secretion of saliva. Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels, activity of ion pumps, and components of the cytoskeleton.
The resting concentration of Ca2+ in the cytoplasm is normally maintained in the range of 10–100 nM. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space and into the endoplasmic reticulum (ER), and sometimes in the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release calcium ions (Ca2+) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.
Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C pathway. Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinases activate the phospholipase C (PLC) enzyme. PLC hydrolyses the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classical second messengers. DAG activates the protein kinase C enzyme, while IP3 diffuses to the endoplasmic reticulum, binds to its receptor (IP3 receptor), which is a Ca2+ channel, and thus releases Ca2+ from the endoplasmic reticulum.
Depletion of calcium from the endoplasmic reticulum will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs). This inflowing calcium current that results after stored calcium reserves have been released is referred to as Ca2+-release-activated Ca2+ current (ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation, although two candidate molecules, Orai1 and STIM1, have been linked by several studies, and a model of store-operated calcium influx, involving these molecules, has been proposed. Recent studies have cited the phospholipase A2 beta, nicotinic acid adenine dinucleotide phosphate (NAADP), and the protein STIM 1 as possible mediators of ICRAC.
Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. Calmodulin may activate calcium-calmodulin-dependent protein kinases, or may act directly on other effector proteins. Besides calmodulin, there are many other Ca2+-binding proteins that mediate the biological effects of Ca2+.
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- Koolman, Jan; Röhm, Klaus-Heinrich (2005). Color Atlas of Biochemistry, New York: Thieme.
- Clapham, D.E. (2007). Calcium Signaling. Cell 131 (6): 1047–1058.
- Csutora, P., et al. (2006). Activation Mechanism for CRAC Current and Store-operated Ca2+ Entry. Journal of Biological Chemistry 281 (46): 34926–34935.
- Moccia, F., et al. (2003). NAADP activates a Ca2+ current that is dependent on F-actin cytoskeleton. The FASEB Journal 17 (13): 1907–1909.
- Baba, Y., et al. (2006). Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. PNAS 103 (45): 16704–16709.
- Petersen, Ole H (2005). Ca2+ signalling and Ca2+-activated ion channels in exocrine acinar cells. Cell Calcium 38 (3–4): 171–200.
Cell physiology: cell signaling
|Types of proteins|
Cell signaling: calcium signaling
IP3 - NAADP - cADPR
|Intracellular calcium store gates|
|Calcium pumps and exchangers||
SERCA - Na/Ca antiport - Ca/H antiport
|calcium binding protein domains||
EF hand domain - C2 domain
|Calcium based molecular switches, and kinases||
Troponin C - CaM - CaM kinases - PKC - NCS
|Intracellular calcium chelators (calcium buffers) and calcium sensors||
Calbindin - S100 - pervalbumin - Calretinin - Calsequestrin - Sarcalumenin - Phospholamban - Synaptotagmins
|Calcium dependent proteases||
|Calcium dependent cytoskeleton remodeling proteins||
|Cell membrane calcium channels|
|Calcium regulated chaperones||
calreticulin - calnexin
|Calcium based adhesion molecules||
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