Signal transduction

Three stages: reception, transduction, response

Cell signalling through a surface receptor happens in three stages. In reception, the signal binds its receptor on the outside of the cell. In transduction, the receptor changes shape, and that change is passed along a chain of molecules inside the cell. In the response, the last molecules in the chain change what the cell is doing.

The chain of molecules is called a signal transduction pathway. "Transduction" means converting a signal from one form into another. Here, a molecule binding on the outside becomes a change in shape, then a burst of small messenger molecules, then a set of switched-on enzymes.

Three kinds of surface receptor

• G protein-coupled receptors (GPCRs) snake through the membrane seven times. When a ligand binds, the receptor activates a G protein on the inside, a protein that acts as a switch by binding either GDP (off) or GTP (on). GPCRs are the largest family of cell-surface receptors; adrenaline and glucagon both use them.
• Receptor tyrosine kinases (RTKs) are receptors that are also enzymes. When ligand binds, two receptors pair up (dimerise) and each adds phosphate groups to tyrosines on the other. Many growth factors, and insulin, use RTKs. (The insulin receptor is unusual: it is already a pair before insulin binds, and binding changes its shape instead.)
• Ligand-gated ion channels open a pore when the ligand binds, letting specific ions such as Na⁺ or Ca²⁺ flow through. They give the fastest responses and are common at synapses.

(Hydrophobic signals such as steroids skip all of this: they cross the membrane and bind intracellular receptors, as you saw in the previous topic.)

Following one pathway: adrenaline in a liver cell

This is the pathway Sutherland uncovered, and it's the one you're most likely to be asked to trace. Two key ideas come up along the way. A second messenger is a small molecule made or released inside the cell that carries the signal onward (the hormone was the first messenger). A protein kinase is an enzyme that adds a phosphate group from ATP to another protein, which usually switches that protein on or off; this is called phosphorylation.

1. 1Adrenaline binds a GPCR on the outside of the liver cell. The receptor changes shape.
2. 2The changed receptor makes a nearby G protein (called Gs, s for stimulatory) swap its GDP for GTP. The G protein's α subunit, now carrying GTP, is active.
3. 3The active α subunit moves along the membrane and switches on adenylyl cyclase, an enzyme in the membrane.
4. 4Adenylyl cyclase converts ATP into cyclic AMP (cAMP), the second messenger. cAMP spreads through the cytoplasm.
5. 5cAMP binds and activates protein kinase A (PKA).
6. 6PKA phosphorylates and activates another kinase, phosphorylase kinase, which in turn phosphorylates and activates glycogen phosphorylase. This enzyme breaks glycogen down into glucose units.
7. 7PKA also phosphorylates glycogen synthase, which switches it off. So the cell stops making glycogen at the same moment it starts breaking it down.
8. 8The response: the liver releases glucose into the blood, fuel for a "fight or flight" situation.

Other second messengers and the Ras route

cAMP isn't the only second messenger. Some GPCRs activate a different G protein (Gq), which switches on phospholipase C. This enzyme splits a membrane lipid called PIP₂ into two messengers: IP₃ and DAG. IP₃ diffuses to the endoplasmic reticulum and opens channels that release stored Ca²⁺ into the cytoplasm. DAG stays in the membrane and, together with Ca²⁺, activates protein kinase C.

Calcium is a powerful messenger because cells normally pump it out of the cytoplasm, keeping its level very low. Opening a channel makes it jump. What Ca²⁺ then does depends on the cell: it triggers contraction in muscle and insulin release in pancreatic β cells.

Many RTKs signal through a small G protein called Ras. Once an RTK has phosphorylated itself, adaptor proteins bind and help Ras swap GDP for GTP. Active Ras then starts a three-kinase relay called the MAP kinase cascade. The last kinase enters the nucleus and phosphorylates transcription factors, switching on genes that drive cell division. This is how many growth factors tell a cell to divide.

Amplification: why so few hormone molecules are enough

Pathway diagrams draw one of each molecule, but that's misleading. At several steps, one activated molecule activates many of the next. One receptor, while it's occupied, can activate many G proteins. One adenylyl cyclase makes many cAMP molecules. Each PKA phosphorylates many phosphorylase kinase molecules, and each of those activates many glycogen phosphorylases, which each release many glucose units.

Multiply these together and the effect is enormous: a small number of hormone molecules can release millions of glucose molecules. This is amplification, and it's why hormones can work at the very low concentrations found in blood.

Multi-step pathways have other advantages too. Each step is a place where the signal can be regulated, and the pathway can branch, so one signal can trigger several responses at once, like the liver cell turning glycogen breakdown on and glycogen synthesis off.

Switching the signal off

A signal that couldn't be switched off would be useless: the cell could never tell whether the hormone was still there. Every step has an off-switch.

• Ligands come off their receptors, so when the hormone level falls, fewer receptors are active.
• G proteins switch themselves off: the α subunit slowly hydrolyses its GTP to GDP. Ras does the same, helped by other proteins.
• Phosphodiesterase converts cAMP to AMP, which can't activate PKA.
• Protein phosphatases remove the phosphate groups that kinases added, reversing their effect.
• Pumps return Ca²⁺ to the endoplasmic reticulum or out of the cell.

Same signal, different response

Adrenaline makes liver cells release glucose. It makes the smooth muscle around some blood vessels contract, and the smooth muscle around others (and in the airways) relax. How can one hormone do opposite things?

The answer is that the response depends on the receiving cell, not on the signal. Different cells make different receptor subtypes for the same hormone, and those subtypes connect to different G proteins and different relay and target proteins. One kind of adrenaline receptor on some smooth muscle works through Gq and Ca²⁺ and causes contraction; another works through Gs and cAMP and causes relaxation. The signal is just the trigger; what gets triggered is set by the proteins that each cell expresses.

Key terms

Signal transduction pathway

The chain of molecules that relays a signal from a receptor to the cell's response.

G protein-coupled receptor (GPCR)

A seven-pass membrane receptor that activates a G protein when ligand binds.

G protein

A switch protein that is active with GTP bound and inactive with GDP bound.

Receptor tyrosine kinase (RTK)

A receptor that dimerises and phosphorylates tyrosines on itself when ligand binds.

Second messenger

A small molecule inside the cell, such as cAMP, Ca²⁺ or IP₃, that carries the signal onward.

Adenylyl cyclase

The membrane enzyme that makes cAMP from ATP.

Protein kinase / phosphatase

An enzyme that adds a phosphate to a protein / one that removes it.

Phosphodiesterase

The enzyme that breaks cAMP down to AMP, ending the signal.

Amplification

Each activated molecule activates many of the next, so the signal grows at each step.

Check yourself

Try answering in your head before you open each answer.

• 1.Caffeine, at high enough concentrations, inhibits phosphodiesterase. Predict what this would do to cAMP levels and glucose release in a liver cell exposed to a small dose of adrenaline.Show answerHide

  cAMP would be broken down more slowly, so it would build up higher and last longer. PKA would stay active longer, and more glucose would be released for longer. (At the amounts in drinks, caffeine's main effect is actually blocking adenosine receptors; phosphodiesterase inhibition needs higher concentrations.)

• 2.A drug stops the G protein α subunit from hydrolysing GTP. What happens to the pathway after adrenaline is removed?Show answerHide

  The α subunit stays in its GTP-bound, active form, so adenylyl cyclase keeps making cAMP even after the hormone has gone. The cell keeps breaking down glycogen: the signal can't be switched off at that step.

• 3.Liver cells and heart muscle cells both have receptors for adrenaline, and both use cAMP. Why does adrenaline make one release glucose and the other beat harder?Show answerHide

  The second messenger is the same, but the proteins that PKA acts on are different in the two cells. Liver cells express glycogen-breaking enzymes; heart cells express proteins that control Ca²⁺ and contraction. The response is set by what each cell has downstream, not by the hormone.