Calcium Signaling
Calcium signalling uses the calcium ion as a near-universal intracellular messenger. Because cells maintain a very low resting concentration of free calcium in the cytoplasm, a controlled rise, produced by influx across the plasma membrane or release from internal stores, serves as a rapid, versatile signal that regulates processes from muscle contraction and secretion to gene expression and cell death.
Definition
Calcium signalling is the use of regulated changes in intracellular free calcium ion concentration, produced by influx through plasma-membrane channels or release from intracellular stores, to control cellular processes through calcium-binding effector proteins.
Scope
The topic covers the sources and handling of intracellular calcium, the channels, pumps, and buffers that shape calcium signals, the role of inositol trisphosphate and calcium-binding proteins, and the spatial and temporal patterning of calcium responses. It is treated as a biochemical and molecular subject within signal transduction mechanisms.
Core questions
- How do cells generate rapid, localised rises in calcium against a low resting level?
- How is the same ion used to control so many different processes?
- How are calcium signals shaped in space and time and then terminated?
Key concepts
- Low resting cytosolic calcium
- Inositol trisphosphate (IP3) receptor
- Ryanodine receptor
- Voltage-gated and store-operated calcium channels
- Calcium pumps and exchangers
- Calmodulin and calcium-binding proteins
- Calcium oscillations and waves
Mechanisms
Cells keep cytosolic free calcium very low by pumping it out across the plasma membrane and into the endoplasmic or sarcoplasmic reticulum. A signal raises calcium either by opening plasma-membrane channels, such as voltage-gated channels, or by releasing calcium from internal stores through inositol trisphosphate receptors, which open in response to the second messenger generated by phospholipase C, and through ryanodine receptors. The resulting rise is detected by calcium-binding proteins, most notably calmodulin, which on binding calcium activate downstream enzymes including calcium/calmodulin-dependent kinases. Depletion of internal stores can trigger store-operated calcium entry to refill them. The signal is shaped into transients, oscillations, and propagating waves by the interplay of release channels, buffers, and uptake systems, and it is terminated when pumps and exchangers restore the low resting concentration. This combination of low background and controlled release lets the same ion encode many distinct messages.
Clinical relevance
Calcium handling is essential to excitable tissues such as muscle and nerve, and disturbances in calcium signalling are implicated in numerous disease processes. This entry describes the mechanisms at a reference level and is not a basis for individual diagnostic or treatment decisions.
Evidence & guidelines
Understanding of calcium signalling rests on biophysical, biochemical, and imaging research and authoritative reviews and textbooks rather than clinical practice guidelines.
History
The recognition that a rise in intracellular calcium triggers physiological responses, beginning with classical studies of muscle contraction, was extended when Berridge and Irvine identified inositol trisphosphate as the second messenger that releases calcium from internal stores. Subsequent work characterised the channels, pumps, and calcium-binding proteins involved and established the rich spatial and temporal patterning of calcium signals as a means of encoding information.
Key figures
- Michael Berridge
- David Clapham
- William Catterall
- Robin Irvine
Related topics
Seminal works
- berridge-2000
- berridge-1984
- clapham-2007
Frequently asked questions
- Why do cells keep resting calcium so low?
- A low resting level means even a small influx or release produces a large relative change, giving a fast, high-contrast signal; it also protects the cell, since chronically high calcium is toxic and can trigger cell death.
- How can one ion control so many different responses?
- Cells encode information in the location, amplitude, timing, and frequency of calcium changes and read them with different calcium-binding proteins, so the same ion can selectively trigger contraction, secretion, gene expression, or other outcomes depending on context.