Calcium (Ca2+) ions are important for cellular signalling, as once they enter the cytosol of the cytoplasm they exert allosteric regulatory effects on many enzymes and proteins. Calcium can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.
Calcium Concentration Regulation
The resting concentration of Ca2+ in the cytoplasm is normally maintained around 100 nM, variously reported as 20,000- to 100,000-fold lower than typical extracellular concentration. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space, the endoplasmic reticulum (ER), and sometimes into the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release Ca2+ ions from intracellular stores, and/or when Ca2+ enters the cell through plasma membrane ion channels.
Phospholipase C Pathway
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 recruits protein kinase C (PKC), attaching it to the plasma membrane
- IP3 diffuses to the endoplasmic reticulum, and binds to an IP3 receptor,
- The IP3 receptor serves as a Ca2+ channel, and releases Ca2+ from the endoplasmic reticulum.
- The Ca2+ ions bind to PKC, activating it.
Depletion of Ca2+ 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.
Movement of Ca2+ ions from the extracellular compartment to the intracellular compartment alters membrane potential. This is seen in the heart, during the plateau phase of ventricular contraction. In this example, Ca2+ acts to maintain depolarization of the heart. Calcium signaling through ion channels is also important in neuronal synaptic transmission.
Calcium as a second messenger
Calcium is a ubiquitous second messenger with wide-ranging physiological roles. 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, neurogenesis, learning and memory as with synaptic plasticity, and secretion of saliva. High levels of cytoplasmic Ca2+ can also cause the cell to undergo apoptosis. Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels, activity of ion pumps, and components of the cytoskeleton.
Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. Calmodulin may activate Ca2+-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+.
In neurons, concomitant increases in cytosolic and mitochondrial Ca2+ are important for the synchronization of neuronal electrical activity with mitochondrial energy metabolism. Mitochondrial matrix Ca2+ levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase, one of the key regulatory enzymes of the Krebs cycle.
In neurons, the ER may serve in a network integrating numerous extracellular and intracellular signals in a binary membrane system with the plasma membrane. Such an association with the plasma membrane creates the relatively new perception of the ER and theme of “a neuron within a neuron.” The ER’s structural characteristics, ability to act as a Ca2+ sink, and specific Ca2+ releasing proteins, serve to create a system that may produce regenerative waves of Ca2+ release that may communicate both locally and globally in the cell. These Ca2+ signals, integrating extracellular and intracellular fluxes, have been implicated to play roles in synaptic plasticity and memory, neurotransmitter release, neuronal excitability and long term changes at the gene transcription level. ER stress is also related to Ca2+ signaling and along with the unfolded protein response, can cause ER associated degradation (ERAD) and autophagy.
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