Calcium signaling

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Shows Ca release from the endoplasmic reticulum through phospholipase C (PLC) pathway. Calcium Signaling Pathway.png
Shows Ca release from the endoplasmic reticulum through phospholipase C (PLC) pathway.

Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca2+ 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.

Contents

Concentration Regulation

The resting concentration of Ca2+ in the cytoplasm is normally maintained around 100 nM. This is 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 Ca2+ ions from intracellular stores, and/or when Ca2+ enters the cell through plasma membrane ion channels. [1] Under certain conditions, the intracellular Ca2+ concentration may begin to oscillate at a specific frequency. [3]

Phospholipase C Pathway

Phospholipase C cleaving PIP2 into IP3 and DAG PLC role in IP3-DAG pathway.tif
Phospholipase C cleaving PIP2 into IP3 and DAG

Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ levels to 500–1,000 nM by opening channels in the ER or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C (PLC) pathway.

  1. Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinases, activate the PLC enzyme.
  2. PLC uses hydrolysis of the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classic secondary messengers.
  3. DAG attaches to the plasma membrane and recruits protein kinase C (PKC).
  4. IP3 diffuses to the ER and is bound to the IP3 receptor.
  5. The IP3 receptor serves as a Ca2+ channel, and releases Ca2+ from the ER.
  6. The Ca2+ bind to PKC and other proteins and activate them. [4]

Depletion from the Endoplasmic Reticulum

Depletion of Ca2+ from the ER will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs). [5] This inflow of Ca2+ is referred to as Ca2+-release-activated Ca2+ current (ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation. Although Orai1 and STIM1, have been linked by several studies, for a proposed model of store-operated calcium influx. Recent studies have cited the phospholipase A2 beta, [6] nicotinic acid adenine dinucleotide phosphate (NAADP), [7] and the protein STIM 1 [8] as possible mediators of ICRAC.

As a Second Messenger

Calcium 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), fertilization, cell growth (proliferation), neurogenesis, learning and memory as with synaptic plasticity, and secretion of saliva. [9] [10] High levels of cytoplasmic Ca2+ can also cause the cell to undergo apoptosis. [11] Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels, [12] activity of ion pumps, and components of the cytoskeleton. [13]

Many of Ca2+ mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. Calmodulin may activate the Ca2+-calmodulin-dependent protein kinases, or may act directly on other effector proteins. [14] Besides calmodulin, there are many other Ca2+-binding proteins that mediate the biological effects of Ca2+.

In Muscle Contractions

Comparison of smooth muscle and skeletal muscle contraction Comparison of smooth muscle and skeletal muscle contraction.png
Comparison of smooth muscle and skeletal muscle contraction

Contractions of skeletal muscle fiber are caused due to electrical stimulation. This process is caused by the depolarization of the transverse tubular junctions. Once depolarized the sarcoplasmic reticulm (SR) releases Ca2+ into the myoplasm where it will bind to a number of calcium sensitive buffers. The Ca2+ in the myoplasm will diffuse to Ca2+ regulator sites on the thin filaments. This leads to the actual contraction of the muscle. [15]

Contractions of smooth muscle fiber are dependent on how a Ca2+ influx occurs. When a Ca2+ influx occurs, cross bridges form between myosin and actin leading to the contraction of the muscle fibers. Influxes may occur from extracellular Ca2+ diffusion via ion channels. This can lead to three different results. The first is a uniform increase in the Ca2+ concentration throughout the cell. This is responsible for increases in vascular diameters. The second is a rapid time dependent change in the membrane potential which leads to a very quick and uniform increase of Ca2+. This can cause a spontaneous release of neurotransmitters via sympathetic or parasympathetic nerve channels. The last potential result is a specific and localized subplasmalemmal Ca2+ release. This type of release increases the activation of protein kinase, and is seen in cardiac muscle where it causes excitation-concentration coupling. Ca2+ may also result from internal stores found in the SR. This release may be caused by Ryaodine (RYRs) or IP3 receptors. RYRs Ca2+ release is spontaneous and localized. This has been observed in a number of smooth muscle tissues including arteries, portal vein, urinary bladder, ureter tissues, airway tissues, and gastrointestinal tissues. IP3 Ca2+ release is caused by activation of the IP3 receptor on the SR. These influxes are often spontaneous and localized as seen in the colon and portal vein, but may lead to a global Ca2+ wave as observed in many vascular tissues. [16]

In Neurons

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 μM levels that are necessary for the activation of isocitrate dehydrogenase, which is one of the key regulatory enzymes of the Krebs cycle. [17] [18]

The ER, in neurons, 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. These may communicate both locally and globally in the cell. These Ca2+ signals integrate extracellular and intracellular fluxes, and have been implicated to play roles in synaptic plasticity, 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. [19]

In Fertilization

Ca2+ influx during fertilization has been observed in many species as a trigger for development of the oocyte. These influxes may occur as a single increase in concentration as seen with fish and echinoderms, or may occur with the concentrations oscillating as observed in mammals. The triggers to these Ca2+ influxes may differ. The influx have been observed to occur via membrane Ca2+ conduits and Ca2+ stores in the sperm. It has also been seen that sperm binds to membrane receptors that lead to a release in Ca2+ from the ER. The sperm has also been observed to release a soluble factor that is specific to that species. This prevents cross species fertilization to occur. These soluble factors lead to activation of IP3 which causes a Ca2+ release from the ER via IP3 receptors. [20] It has also been seen that some model systems mix these methods such as seen with mammals. [21] [22] Once the Ca2+ is released from the ER the egg starts the process of forming a fused pronucleus and the restart of the mitotic cell cycle. [23] Ca2+ release is also responsible for the activation of NAD+ kinase which leads to membrane biosynthesis, and the exocytosis of the oocytes cortical granules which leads to the formation of the hyaline layer allowing for the slow block to polyspermy.

See also

Related Research Articles

Signal transduction Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

Na<sup>+</sup>/K<sup>+</sup>-ATPase Enzyme found in the membrane of all animal cells

Na⁺/K⁺-ATPase is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.

Calmodulin

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of all muscle cell types, and in fertilization. Many enzymes require calcium ions as a cofactor, including several of the coagulation factors. Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation.

Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger; see calcium in biology for more details). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

Muscle contraction Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding a heavy book or a dumbbell at the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

Calcium release-activated channels (CRAC) are specialized plasma membrane Ca2+ ion channels. When calcium ions (Ca2+) are depleted from the endoplasmic reticulum (a major store of Ca2+) of mammalian cells, the CRAC channel is activated to slowly replenish the level of calcium in the endoplasmic reticulum. The Ca2+ Release-activated Ca2+ (CRAC) Channel (CRAC-C) Family (TC# 1.A.52) is a member of the Cation Diffusion Facilitator (CDF) Superfamily. These proteins typically have between 4 and 6 transmembrane α-helical spanners (TMSs). The 4 TMS CRAC channels arose by loss of 2TMSs from 6TMS CDF carriers, an example of 'reverse' evolution'.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+-Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

Visual phototransduction Sensory transduction of the visual system

Visual phototransduction is the sensory transduction of the visual system. It is a process by which light is converted into electrical signals in the rod cells, cone cells and photosensitive ganglion cells of the retina of the eye. This cycle was elucidated by George Wald (1906–1997) for which he received the Nobel Prize in 1967. It is so called "Wald's Visual Cycle" after him.

T-tubule Invagination of the plasma membrane of a muscle cell that extends inward from the cell surface around each myofibril; the ends of T-tubules make contact with the sarcoplasmic reticulum membrane

T-tubules are extensions of the cell membrane that penetrate into the centre of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration.

A calcium spark is the microscopic release of calcium (Ca2+) from a store known as the sarcoplasmic reticulum (SR), located within muscle cells. This release occurs through an ion channel within the membrane of the SR, known as a ryanodine receptor (RyR), which opens upon activation. This process is important as it helps to maintain Ca2+ concentration within the cell. It also initiates muscle contraction in skeletal and cardiac muscles and muscle relaxation in smooth muscles. Ca2+ sparks are important in physiology as they show how Ca2+ can be used at a subcellular level, to signal both local changes, known as local control, as well as whole cell changes.

TRPC is a family of transient receptor potential cation channels in animals.

STIM1

Stromal interaction molecule 1 is a protein that in humans is encoded by the STIM1 gene. STIM1 has a single transmembrane domain, and is localized to the endoplasmic reticulum, and to a lesser extent to the plasma membrane.

STIM2

Stromal interaction molecule 2 (STIM2) is a protein that in humans is encoded by the STIM2 gene.

Oocyteactivation is a series of processes that occur in the oocyte during fertilization.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Calcium plays a crucial role in regulating the events of cellular division. Calcium acts both to modulate intracellular signaling as a secondary messenger and to facilitate structural changes as cells progress through division. Exquisite control of intracellular calcium dynamics are required, as calcium appears to play a role at multiple cell cycle checkpoints.

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Further reading