Intracellular Calcium and Second Messengers

Second messengers are small intracellular molecules and ions that relay and amplify signals received at the cell surface. Calcium ions are the most versatile of these: cells hold cytosolic calcium very low and release it in controlled bursts to trigger responses ranging from muscle contraction to secretion. Alongside calcium, messengers such as cyclic AMP and inositol trisphosphate carry signals from activated receptors into the cell interior.

Definition

A second messenger is a small intracellular molecule or ion whose concentration changes in response to receptor activation and which relays the signal to downstream effectors; intracellular calcium is a central example, kept at low resting cytosolic levels and mobilized to trigger cellular responses.

Scope

The entry covers the concept of the second messenger, the sources and handling of intracellular calcium (entry across the plasma membrane and release from internal stores), the inositol-phospholipid pathway that generates inositol trisphosphate and diacylglycerol, and other messengers such as cyclic nucleotides. It treats second-messenger signaling as a reference topic in cell biology and is not clinical guidance.

Core questions

• Why do cells keep cytosolic calcium so low at rest?
• From where is signaling calcium drawn, and how is it released?
• How does inositol trisphosphate link surface receptors to calcium release?
• How are calcium and other second-messenger signals shaped in space and time?

Key concepts

• Second messenger concept
• Low resting cytosolic calcium
• Calcium entry across the plasma membrane
• Calcium release from internal stores
• Inositol trisphosphate and diacylglycerol
• Cyclic nucleotides (cAMP, cGMP)
• Spatial and temporal patterning of calcium signals

Key theories

Inositol trisphosphate (IP3) signaling pathway

Receptor activation of phospholipase C cleaves a membrane phospholipid into IP3 and diacylglycerol; IP3 diffuses to the endoplasmic reticulum and opens calcium-release channels, linking surface signals to a rise in cytosolic calcium.

Mechanisms

Cells maintain cytosolic calcium far below extracellular and stored levels by pumps and exchangers, creating a steep gradient that can be exploited for signaling. When a stimulus arrives, calcium enters through plasma-membrane channels or is released from internal stores, chiefly the endoplasmic (and in muscle, sarcoplasmic) reticulum. A major release pathway begins when receptors activate phospholipase C, which cleaves a membrane phospholipid into inositol trisphosphate (IP3) and diacylglycerol; IP3 opens reticular calcium-release channels while diacylglycerol activates protein kinase C. The resulting calcium rise binds effector proteins to trigger responses, and is shaped into transient spikes, waves, or oscillations whose timing and location encode information. Other second messengers, notably cyclic AMP and cyclic GMP generated downstream of distinct receptors, relay signals in parallel. Signals are terminated by pumping calcium back into stores or out of the cell and by degrading cyclic nucleotides, resetting the system.

Clinical relevance

Calcium and second-messenger signaling underlie fundamental physiology such as muscle contraction, neurotransmitter and hormone secretion, and gene-expression responses, so understanding them is foundational for interpreting many cellular processes in health and disease. This entry describes signaling mechanisms for reference and is not a basis for diagnosis or treatment.

History

The second-messenger concept arose from the mid-twentieth-century discovery of cyclic AMP as an intracellular relay of hormone action. Calcium was subsequently recognized as a near-universal intracellular signal, and the 1980s and 1990s clarified the inositol-phospholipid pathway, identifying IP3 as the messenger that releases calcium from internal stores. Later work emphasized the spatial and temporal patterning of calcium signals — spikes, waves, and oscillations — as a means of encoding distinct responses.

Key figures

• Michael J. Berridge
• Robin F. Irvine

Seminal works

• berridge-2000
• berridge-irvine-1993

Frequently asked questions

What is a second messenger?

A second messenger is a small intracellular molecule or ion, such as calcium, cyclic AMP, or inositol trisphosphate, whose level changes after a receptor is activated and which carries the signal onward to effectors inside the cell.

Why do cells keep cytosolic calcium so low?

Keeping resting cytosolic calcium very low creates a steep gradient against the extracellular space and internal stores, so that opening calcium channels produces a rapid, sharp rise that can act as a precise signal.