Signal transduction and feedback

Cells signal each other at three ranges. Neighbors in direct contact pass signals through junctions between them (gap junctions in animals, plasmodesmata in plants) or through molecules on their surfaces. Local signals diffuse a short distance to nearby cells, as growth factors and neurotransmitters do. Hormones travel in the blood to target cells anywhere in the body. Only a cell with a receptor that fits the signal responds.

Every signaling pathway has three stages. Reception: a signal molecule, the ligand, binds a receptor protein, and the receptor changes shape. Transduction: that shape change starts a chain of relay molecules inside the cell. Response: the last relay molecule changes what the cell does, for example by switching an enzyme on, opening a channel or turning genes on or off.

Where the receptor sits depends on the signal. Large or polar signals, such as insulin and epinephrine, cannot cross the bilayer, so they bind receptors in the plasma membrane. Small nonpolar signals, such as the steroid hormones testosterone and cortisol, cross the membrane and bind intracellular receptors; the hormone and receptor together often act as a transcription factor that turns genes on.

Three common membrane receptors: a G protein-coupled receptor activates a G protein, which switches on an enzyme that makes a second messenger such as cyclic AMP (cAMP). A receptor tyrosine kinase pairs up, its two halves add phosphate groups to each other, and the phosphorylated receptor activates relay proteins. A ligand-gated ion channel opens and lets ions such as sodium or calcium flow through.

In transduction, protein kinases often pass the signal along by adding a phosphate group to the next protein in line, a phosphorylation cascade. Phosphatases remove those phosphates and help turn the pathway off. Because one active enzyme can activate many molecules of the next, a few signal molecules can produce a large response: the signal is amplified. For example, epinephrine binding a liver cell leads to cAMP, which activates protein kinase A, which starts the cascade that switches on the enzyme that breaks glycogen into glucose.

A change to any part of a pathway changes the response. A receptor that cannot bind its ligand blocks the response. A relay protein stuck in its active form keeps signaling with no ligand at all. Different cells can respond differently to the same signal because they have different receptors or different relay and target proteins.

Feedback links a response back to its cause. In negative feedback, the response reverses the change that triggered it and holds a variable near a set point. After a meal, blood glucose rises; the pancreas releases insulin; body cells take up glucose and the liver stores it as glycogen; glucose falls, and insulin release slows. Between meals, glucagon from the pancreas makes the liver break glycogen down and release glucose. In positive feedback, the response adds to the change and pushes the process to an end point. During childbirth, pressure on the cervix triggers release of the hormone oxytocin, which strengthens contractions, which press harder and trigger more oxytocin, until the baby is born. Ripening fruit gives off ethylene gas, which speeds ripening in the same and nearby fruit.

To explain a signaling result, walk the chain: the ligand binds the receptor, the receptor activates the first relay molecule, each relay molecule activates the next, and the last one causes the response. To predict the effect of a block, find the broken link: steps before it still happen, steps after it do not. A link stuck in its active form does the reverse: every step after it runs even with no signal.

To explain feedback, name the variable, say which way it changed, and say whether the response pushes it back (negative) or further (positive).