Calcium Signalling
Ca2+ signalling is a carefully controlled process.
A stimulus acts by generating Ca2+-mobilising signals that act in various ON mechanisms to trigger an increase in the intracellular Ca2+ concentration.
This increased level of Ca2+ stimulates various Ca2+-sensitive processes.
The response is terminated by OFF mechanisms that restore [Ca2+] to its resting level.
Ca2+-mobilising signals are generated by stimuli acting through cell-surface receptors, including G-protein (G)-linked receptors, and receptor tyrosine kinases (RTK).
The signals generated include inositol-1,4,5-triphosphate (Ins(1,4,5)P3), generated by the hydrolysis of phosphatidylinositol-4,5-bisphosphate by a family of phospholipase C enzymes; and cyclic ADP ribose (cADPR) and nicotinic acid dinucleotide phosphate (NAADP), both generated by nicotinamide-adenine dinucleotide (NAD) and NADP by ADP ribosyl cyclase, and sphingosine-1-phosphate (S1P).
ON Mechanisms include plasma membrane Ca2+ channels, which response to transmitters or to membrane depolarisation. They also include intracellular Ca2+ channels—the (Ins(1,4,5)P3) receptor, the ryanodine receptor (RYR), NAADP receptor and sphingolipid Ca2+ release-mediated protein of the ER (SCaMPER).
OFF Mechanisms pump Ca2+ out of the cytoplasm via the Na+/Ca2+ exchanger and the plasma membrane Ca2+ ATPase (PMCA) whilst the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pumps Ca2+ back into the ER/SR.
Calcium Dynamics and Homeostasis:
Cytosolic calcium concentration is maintained at very low levels.
Resting cytosolic calcium is typically around 100 nM.
Extracellular calcium concentration is approximately 2 mM, creating a steep electrochemical gradient.
Calcium enters the cytoplasm through the plasma membrane.
Entry occurs via voltage-gated calcium channels.
Entry occurs via ligand-gated calcium channels.
Entry occurs via G-protein-regulated calcium channels.
Calcium is also released from intracellular stores.
The endoplasmic reticulum is the main intracellular calcium store.
Inositol 1,4,5-trisphosphate receptors release calcium following GPCR activation.
Ryanodine receptors release calcium in response to rises in cytosolic calcium.
This process is known as calcium-induced calcium release.
Calcium is removed from the cytoplasm to maintain homeostasis.
Plasma membrane calcium ATPases pump calcium out of the cell.
The sodium–calcium exchanger extrudes calcium using the sodium gradient.
The sarco-endoplasmic reticulum calcium ATPase pumps calcium back into the endoplasmic reticulum.
Mitochondria transiently take up calcium and act as dynamic buffers.
These mechanisms allow tight control of calcium signal amplitude, duration, and localisation.
Calcium Sensors and Calcium-Sensitive Processes:
Calcium signals are detected by calcium-binding proteins known as calcium sensors.
These proteins undergo conformational changes upon calcium binding.
Conformational changes allow interaction with specific target proteins.
Calmodulin is a key calcium sensor.
It regulates enzymes, ion channels, and transcription factors.
It plays a central role in decoding calcium signals.
Calcium-dependent protein kinases are activated by calcium binding.
These kinases phosphorylate downstream targets.
Calcium regulates a wide range of cellular processes.
These include muscle contraction.
These include neurotransmitter release and secretion.
These include metabolic regulation.
These include gene transcription.
These include apoptosis.
Signalling specificity depends on the type, localisation, and calcium affinity of the sensor proteins.
Crosstalk Between Calcium and Other Signalling Pathways:
Calcium signalling interacts with multiple intracellular signalling pathways.
Calcium interacts with cyclic AMP signalling.
Some adenylyl cyclase isoforms are activated by calcium.
Other adenylyl cyclase isoforms are inhibited by calcium.
Cyclic AMP feeds back to regulate calcium channels and calcium pumps.
Calcium interacts with nitric oxide signalling.
Calcium activates nitric oxide synthase.
Nitric oxide functions as a local signalling molecule.
Nitric oxide activates guanylyl cyclase.
Guanylyl cyclase increases cyclic GMP levels.
Cyclic GMP can regulate calcium channel activity.
Calcium interacts with phosphoinositide 3-kinase signalling.
PI3 kinase signalling generates phosphatidylinositol-3,4,5-trisphosphate.
Lowering phosphatidylinositol-3,4,5-trisphosphate reduces calcium influx.
Calcium can exert feedback control over its own signalling.
Calcium activates phospholipase C.
This increases inositol 1,4,5-trisphosphate production.
Calcium directly modulates calcium channels and calcium pumps.
Spatial and Temporal Organisation of Calcium Signalling:
Calcium signalling is organised in both space and time.
Localised calcium signals can occur without global cytosolic changes.
Small, brief calcium release events are known as sparklets, sparks, or blips.
These events arise from the opening of small numbers of calcium channels.
Local signals can integrate into larger events.
Summation of local events can generate calcium waves.
Calcium waves coordinate responses across cells or tissues.
Temporal patterning allows calcium signals to encode information.
Signal frequency and duration are key determinants of downstream responses.
Calcium Microdomains:
Calcium microdomains are localised regions of elevated calcium concentration.
They form close to open calcium channels.
They allow selective activation of nearby targets.
Microdomains are organised by multimolecular protein complexes.
In cardiac cells, calcium microdomains are generated by ryanodine receptor 2 complexes.
These microdomains are essential for excitation–contraction coupling.
In neurons, calcium microdomains involve NMDA receptor and inositol 1,4,5-trisphosphate receptor complexes.
These microdomains regulate synaptic signalling.
At synapses, calcium microdomains control synaptic vesicle fusion.
This enables rapid and precise neurotransmitter release.
Microdomains increase signalling specificity and prevent inappropriate global calcium elevation.