Second messenger system

Second messengers are small molecules produced inside a cell after that cell has been exposed to an external signaling molecule—the first messenger. These internal signals drive a range of cellular changes, including growth, movement, survival, programmed death, and electrical activity. They are a key step in the chain of events that carry a signal from the cell surface to its interior.

First messengers are typically hydrophilic substances like peptide hormones and neurotransmitters—for example, epinephrine, growth hormone, and serotonin—that cannot cross the cell’s lipid membrane. (Steroid hormones, which are hydrophobic, can enter cells directly.) To get around this, the cell uses signal transduction mechanisms that convert the first messenger’s arrival into second messengers, which then propagate the message inside the cell. A major advantage of this system is that second messengers can link to multi-step kinase cascades, greatly amplifying the original signal. For instance, the RasGTP pathway connects to the MAPK cascade, boosting the activation of transcription factors like Myc and CREB.

Earl Wilbur Sutherland Jr. discovered second messengers, earning the 1971 Nobel Prize. He observed that epinephrine made liver cells turn glycogen into glucose, but epinephrine alone couldn’t do it—it required a second messenger, cyclic AMP, to trigger the conversion. The detailed mechanisms were later worked out by Martin Rodbell and Alfred G. Gilman, who shared the 1994 Nobel Prize.

Second messengers are produced and activated by enzymes—such as cyclases that make cyclic nucleotides—or by ion channels that open to let in metal ions like calcium. These small molecules then bind to and activate protein kinases, ion channels, and other proteins, continuing the signaling cascade.

There are three basic types of second messenger molecules:

- **Hydrophobic molecules** (water-insoluble), like diacylglycerol and phosphatidylinositols, which stay associated with membranes and diffuse from the plasma membrane into the intermembrane space to reach membrane-bound effector proteins. - **Hydrophilic molecules** (water-soluble), such as cAMP, cGMP, IP₃, and Ca²⁺, which float freely in the cytosol. - **Gases**, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S), which can diffuse through both the cytosol and across cell membranes.

These messengers share common features: they can be synthesized or released and then broken down by specific enzymes or ion channels; some (like calcium) are stored in organelles and released on demand; and their production and destruction can be localized, letting the cell control the timing and reach of the signal.

Several second messenger systems exist—such as the cAMP system, the phosphoinositol system, and the arachidonic acid system—but they follow a similar overall pattern. A ligand binds to a cell surface receptor, causing a shape change in the receptor. This change can directly produce active second messengers or, in the case of G protein-coupled receptors, exposes a binding site for a G-protein. The G-protein (named for its binding of GDP and GTP) is anchored to the inner membrane and has three subunits: alpha, beta, and gamma. It acts as a transducer.

When the G-protein binds the activated receptor, it swaps a GDP molecule on its alpha subunit for a GTP. This causes the alpha subunit to break away from the beta and gamma subunits, all remaining membrane-bound. The free alpha subunit moves along the membrane until it contacts a primary effector. That effector then creates a signal that can diffuse inside the cell—the second messenger. The second messenger may then activate a secondary effector, with effects that depend on the specific system.

Calcium ions are a key second messenger, involved in muscle contraction, fertilization, and neurotransmitter release. They are normally stored in organelles like the endoplasmic reticulum and are released during signal transduction. The enzyme phospholipase C produces diacylglycerol and inositol trisphosphate; the latter increases calcium ion permeability in the membrane. Active G-proteins also open calcium channels to let calcium enter from outside. Diacylglycerol, the other product, activates protein kinase C, which helps activate cAMP.