Second messengers and the fight-or-flight response

When something startles you, your heart pounds and your muscles are ready to move within seconds. The hormone behind this, epinephrine, never enters its target cells. It acts through a G-protein-coupled receptor and a small molecule called cAMP that spreads the message inside.

First and second messengers

A signaling molecule that binds a receptor on the cell surface is sometimes called a first messenger. It stays outside the cell.

Many pathways that start at a G-protein-coupled receptor (GPCR), a receptor that hands its signal to a partner protein called a G protein, then produce a small molecule or ion that carries the signal through the inside of the cell. That inside carrier is a second messenger. Second messengers take effect within seconds to minutes and usually wear off soon after, so cells rely on them for quick, brief responses.

Making and breaking down cAMP

A key second messenger is cyclic AMP (cAMP), and calcium ions (Ca²⁺) are another common one. A G protein is active while it holds GTP, and some G proteins have an α subunit that binds and switches on an enzyme in the plasma membrane called adenylyl cyclase. Adenylyl cyclase makes cAMP from ATP. A different enzyme converts cAMP to AMP, which ends its signal; this enzyme is phosphodiesterase.

cAMP switches on an enzyme called protein kinase A (PKA). Like other kinases, PKA attaches phosphate groups to proteins, which changes their activity. PKA is built from four subunits: two catalytic subunits that do the phosphorylating, and two regulatory subunits that hold the catalytic subunits in check while attached to them.

The epinephrine pathway

Epinephrine, also called adrenaline, is released when you face stress or danger. It prepares the body to stand and fight or to run, so it’s known as the fight-or-flight hormone. In its target cells, the signal passes along this chain:

Signal transduction here begins when the G protein is activated and ends with active PKA. The phosphorylation of target proteins, which changes what they do, is the cellular response.

The response in skeletal muscle

Skeletal muscle cells store glucose in long chains of glucose units called glycogen. During fight or flight they need that glucose to make ATP, which powers contraction. Active PKA phosphorylates two enzymes, with opposite effects:

• Phosphorylase kinase is activated. It then phosphorylates and activates a second enzyme, glycogen phosphorylase, which breaks glycogen down by releasing glucose units (as glucose-phosphate) one at a time from the ends of the chain.
• Glycogen synthase, the enzyme that builds glycogen, is inhibited.

So glycogen breakdown speeds up while glycogen building stops. The muscle cell gets a supply of glucose to burn for ATP, and you’re ready to fight or flee.

Check yourselfEpinephrine never enters a muscle cell. Trace the chain of events from epinephrine binding to glycogen breakdown.

Epinephrine binds a GPCR, which activates a G protein. The G protein’s α subunit activates adenylyl cyclase, which makes cAMP from ATP. cAMP frees PKA’s catalytic subunits, which phosphorylate and activate phosphorylase kinase. Phosphorylase kinase then phosphorylates and activates glycogen phosphorylase, which breaks glycogen down.