Second Messenger Systems
Second messengers are small intracellular molecules that relay and amplify signals received at the cell surface, converting receptor activation into widespread chemical change inside the cell.
Definition
A second messenger is a small intracellular signaling molecule whose concentration rises in response to receptor activation and which relays the signal by activating downstream effectors; second messenger systems are the pathways built around them.
Scope
This topic covers the major second messengers—cyclic AMP and cyclic GMP, calcium ions, and the products of phosphoinositide hydrolysis—their generation and removal, and the downstream enzymes such as protein kinases that they activate, illustrating signal amplification and integration.
Core questions
- How is cyclic AMP produced and what does it activate?
- Why are calcium ions effective second messengers?
- How does phosphoinositide hydrolysis generate two messengers at once?
- How are second messenger levels kept transient?
Key theories
- Cyclic AMP as a second messenger
- Sutherland showed that hormone binding raises intracellular cyclic AMP, which activates downstream kinases, establishing the paradigm that a surface signal is relayed by a diffusible small molecule.
- Phosphoinositide signaling
- Berridge and Irvine showed that hydrolysis of a membrane phospholipid yields inositol trisphosphate and diacylglycerol, two messengers that release calcium and activate protein kinase C, branching one signal into two arms.
Mechanisms
Adenylyl cyclase converts ATP to cyclic AMP, which activates protein kinase A; phosphodiesterases degrade cyclic AMP to end the signal. Phospholipase C cleaves a membrane phosphoinositide into inositol trisphosphate, which opens calcium channels, and diacylglycerol, which activates protein kinase C. Calcium itself acts through binding proteins such as calmodulin. In each system, generation is balanced by rapid removal so that messenger levels track the incoming signal.
Clinical relevance
Second messenger chemistry exemplifies amplification and branching in molecular networks and is foundational to chemical biology. The treatment is descriptive and non-prescriptive.
History
Sutherland's discovery of cyclic AMP opened the field; the phosphoinositide pathway was elucidated by Berridge, Irvine, and others in the 1980s, and Nishizuka's identification of protein kinase C linked diacylglycerol to downstream phosphorylation.
Key figures
- Earl Sutherland
- Michael Berridge
- Yasutomi Nishizuka
Related topics
Seminal works
- sutherland1972
- berridge1984
- nelson2021
Frequently asked questions
- Why are second messengers useful?
- They let a signal acting at the cell surface spread quickly throughout the cell and be amplified, since one activated enzyme can generate many messenger molecules that each activate further effectors.
- How does calcium serve as a signal if it is always present?
- Cells keep cytosolic calcium very low at rest, so a regulated rise produces a sharp, transient signal that binding proteins detect, after which pumps restore the low resting level.