Calcium signaling

Calcium 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.^[1][2] 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 calcium ions (Ca²⁺) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.^[1]

Phospholipase C Pathway

Phospholipase C cleaving PIP2 into IP3 and DAG

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.^[3]

Depletion of calcium from the endoplasmic reticulum will lead to Ca²⁺ entry from outside the cell by activation of "Store-Operated Channels" (SOCs).^[4] 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,^[5] nicotinic acid adenine dinucleotide phosphate (NAADP),^[6] and the protein STIM 1^[7] as possible mediators of ICRAC.

Movement of calcium 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, calcium 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 (as Ca²⁺) is a ubiquitous second messenger with wide-ranging physiological roles.^[2] 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.^[8][9] High levels of cytoplasmic calcium can also cause the cell to undergo apoptosis.^[10] Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels,^[11] activity of ion pumps, and components of the cytoskeleton.^[12]

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.^[13] Besides calmodulin, there are many other Ca²⁺-binding proteins that mediate the biological effects of Ca²⁺.

In neurons, concomitant increases in cytosolic and mitochondrial calcium are important for the synchronization of neuronal electrical activity with mitochondrial energy metabolism. Mitochondrial matrix calcium 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.^[14][15]

In the neuron, 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.^[16]

See also

• Nanodomain

References

Further reading

• Petersen, Ole H (2005). "Ca²⁺ signalling and Ca²⁺-activated ion channels in exocrine acinar cells". Cell Calcium. 38 (3–4): 171–200. PMID 16107275. doi:10.1016/j.ceca.2005.06.024. 

Wikimedia Commons has media related to Calcium signaling.