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Educerie · AP · Biology

AP Biology 4.2 Introduction to Signal Transduction

In one breath

  • A signal transduction pathway has three stages: reception, transduction, response.
  • A ligand, which can be a protein or a small molecule, binds the ligand-binding domain of a specific receptor.
  • Hydrophilic ligands use surface receptors and never enter the cell; small hydrophobic ones such as steroids cross the membrane to receptors in the cytoplasm or nucleus.
  • Binding changes the receptor's shape, including its intracellular domain, and starts transduction.
  • In a G protein-coupled receptor pathway, the receptor switches on a G protein (GDP swapped for GTP), which activates adenylyl cyclase to make the second messenger cAMP, which activates protein kinase A and a phosphorylation cascade.
  • Each enzyme acts on many molecules, so the signal is amplified.
  • Every relay is switched off again (GTP hydrolysed, cAMP broken down, phosphates removed).
  • Responses include gene expression, secretion, growth and changes in enzyme activity.
  • Ligand-gated channels open or close when their ligand binds.

What you must be able to do

  • Describe the three stages of a signal transduction pathwayOrder the steps of a pathway model
  • Describe how a ligand is recognised by the binding domain of a receptor"Explain why only cells with the receptor respond"
  • Say where receptors are found, and which kind of ligand uses each"Predict where the receptor for this hydrophobic hormone is"
  • Describe a G protein-coupled receptor pathway with a second messengerName the role of cAMP, the G protein or a kinase in a model
  • Explain how a phosphorylation cascade relays and amplifies a signalA calculation of amplification, or "explain how one hormone molecule causes a large response"
  • Describe how a ligand-gated channel worksPredict what happens to ion flow when the ligand binds

Once you have read the note, tick off each one you can do in Check your understanding.

In the exam. Section I multiple choice, very often as a model of a pathway (receptor, G protein, second messenger, kinases) where you name a component's role or trace the order of steps. In Section II, Analyze Model or Visual Representation asks you to describe what one labelled step does; Conceptual Analysis asks you to describe how a signal outside the cell produces a response inside; and Interpreting and Evaluating Experimental Results uses data such as cAMP concentration after adding a hormone.

1Reception: a ligand meets its receptor

A receptor has a ligand-binding domain, a region whose shape and chemical groups fit one ligand. Binding is like an enzyme and its substrate: specific, weak non-covalent bonds, reversible. A ligand can be a peptide or protein (insulin, growth hormone) or a small molecule (epinephrine, a steroid).

Where the receptor sits depends on whether the ligand can cross the membrane (Figure 1).

Figure 1. Where the receptor sits depends on whether the ligand can cross the membrane outside cytoplasm hydrophilic ligand: stays outside hydrophobic amino acids hydrophilic amino acids transmembrane receptor steroid: hydrophobic diffuses through the bilayer intracellular receptor: hydrophilic surface
Figure 1 · Where the receptor sits depends on whether the ligand can cross the membrane
  • Hydrophilic or large ligands (proteins, peptides, charged molecules) cannot cross the hydrophobic core of the bilayer. Their receptors are on the surface: proteins that span the membrane, with the binding domain outside and an intracellular domain in the cytoplasm.
  • Small hydrophobic ligands (steroid hormones such as testosterone and estrogen) diffuse straight through the bilayer. Their receptors are inside, in the cytoplasm or the nucleus. The hormone–receptor complex often acts directly on DNA, switching particular genes on.

The point to hold on to: for a surface receptor, the ligand never enters the cell. Only the information does, as a change in the receptor's shape.

2Transduction: a G protein-coupled receptor and cAMP

G protein-coupled receptors (GPCRs) are the largest family of receptor proteins in eukaryotes. Each is a single protein that crosses the membrane seven times. On the inside it works with a G protein, a relay protein that is off when it carries GDP and on when it carries GTP. The liver's response to epinephrine (adrenaline) is the example to know. Step through Figure 2.

Figure 2. How epinephrine acts on a liver cell through a G protein and cAMP outside: blood cytoplasm receptor adenylyl cyclase α G protein epinephrine GDP out, GTP in α ATP cAMP protein kinase glycogen glycogen broken down glucose to the blood
Figure 2 · How epinephrine acts on a liver cell through a G protein and cAMP
1

Reception. Epinephrine, carried in the blood, binds the ligand-binding domain of a GPCR on the liver cell's surface. It stays outside the cell.

2

The receptor changes shape. The change reaches the intracellular domain, which now activates a nearby G protein: the G protein releases GDP and binds GTP, which switches it on.

3

The G protein relays the signal. The active part of the G protein moves along the inner face of the membrane to an enzyme, adenylyl cyclase, and activates it.

4

A second messenger. Adenylyl cyclase converts ATP into cyclic AMP (cAMP). One enzyme makes many cAMP molecules, which spread through the cytoplasm. cAMP is the second messenger: epinephrine was the first.

5

A kinase is switched on. cAMP binds and activates protein kinase A, an enzyme that adds phosphate groups to other proteins.

6

The cascade and the response. The kinase phosphorylates the next enzyme in the chain, which phosphorylates the enzyme that breaks glycogen down. Glycogen is broken into glucose, which leaves the cell for the blood.

3Phosphorylation cascades: relay and amplification

A protein kinase is an enzyme that transfers a phosphate group from ATP to another protein. The added phosphate changes the protein's shape, which switches its activity on (or sometimes off). In a phosphorylation cascade, kinase 1 phosphorylates kinase 2, which phosphorylates kinase 3, and so on, until the last one phosphorylates the protein that produces the response.

Why so many steps? Two reasons.

Amplification. Each active enzyme in the chain acts on many molecules of the next before it is switched off. An illustrative calculation, with our own round numbers: one epinephrine molecule keeps its receptor active long enough to switch on 10 G proteins; each activated adenylyl cyclase makes 100 cAMP molecules; every 2 cAMP molecules activate one kinase, and each kinase phosphorylates 100 molecules of the next enzyme.

1×10×100×12×100=5×104 1 \times 10 \times 100 \times \tfrac{1}{2} \times 100 = 5 \times 10^{4}

So one hormone molecule at the surface becomes 50,000 activated enzyme molecules, and each of those goes on to break down many glucose units from glycogen. Real numbers vary, but the logic, multiplying at each step, is what questions test.

Control points. Each step is a place where the cell can adjust the response or where another pathway can feed in.

Switching off. A response must stop when the signal stops, so every relay molecule is recycled between an active and an inactive form. The G protein hydrolyses its GTP to GDP and switches itself off. Enzymes called phosphodiesterases convert cAMP to AMP, which is inactive. Protein phosphatases remove phosphate groups from the kinases. Without the ligand, the receptor releases it and returns to its resting shape. So a pathway is on only while the ligand keeps arriving.

Transduction is a relay of shape changes: each molecule switches the next on, many times over, and is then switched off again.

4Responses

The final molecule in the pathway changes the cell in one of a few ways the CED names:

  • Gene expression: a transcription factor is activated and genes are switched on or off (steroid hormones; many growth signals).
  • Secretion: the cell releases a product, such as an enzyme or a hormone.
  • Cell growth, including division.
  • Enzyme activity: an enzyme already present is switched on or off, as in glycogen breakdown. This is fast because no new protein must be made.

Hormones are the classic long-distance signalling molecules, travelling in the blood (topic 4.1), but the pathway inside the target cell works the same way for a local signal.

5Ligand-gated channels

Some receptors are channels. A ligand-gated ion channel is a membrane protein with a pore and a binding site. When the ligand binds, the protein changes shape and the channel opens (or, for some, closes), changing the flow of particular ions across the membrane. At the junction between a motor neuron and a muscle fibre, acetylcholine binds such a channel; it opens, sodium ions flow into the muscle cell, and the change in charge starts contraction. The response is very fast, because the receptor itself is the effector: there is no cascade.

Practice questions

8 questions on this note, from easy to hard. Each one you get right lights a star of this topic's constellation.