Receptors and Other Drug Targets

Last post before the test! Joy :(

For each of the 4 superfamilies of receptor, be able to describe major characteristic features including
–  mechanism of signal transduction
–  receptor location
–  effector protein(s)
–  time scale of action
Provide at least one detailed example of a drug that acts via each of the 4 receptor superfamilies 

Ion-channel receptors

Ion-channel receptors, as their name suggests, are receptors that are ion channels. When activated by an agonist (usually a fast neurotransmitter), they open, allowing ions to flow through them. (Ions generally do not cross the cell membrane as they are charged particles.) They are located in the cell membrane, with both their C and N-termini located extracellularly. As ion flow occurs rapidly, their mechanism of action likewise occurs rapidly.

One example of a drug that acts on ion-channel receptors is Pancuronium. It antagonises nicotinic ACh receptors, which are also Na+ channels. Since it is an antagonist, it prevents the Na+ channels from opening and allowing Na+ from crossing the cell membrane. This stops neurons from producing their action potentials, and thus results in local anaesthesia.

G-protein coupled receptors

G-protein coupled receptors have their effects by interacting with G-proteins, which in turn react with other second messengers in the cell. I've spoken about G-proteins before, but just a quick recap: G-proteins are proteins that bind GTP (guanosine triphosphate). When this GTP is hydrolysed, only GDP (guanosine diphosphate) remains. G-protein coupled receptors act as GEFs (guanosine exchange factors), which, when bound by an agonist, get rid of the GDP on the G-protein so that it can be replaced with a fresh GTP molecule, thus activating the G-protein. G-proteins have three subunits (alpha, beta and gamma) which can interact with other effector proteins that release second messengers (for example Gα_s activates adenylate cyclase, which produces cAMP).

G-protein coupled receptors are also located in the cell membrane. However, while their N-terminus is also located extracellularly, their C-terminus is located intracellularly. The intracellular region reacts with the G-protein.

Most G-protein coupled receptors respond to hormones or slow neurotransmitters. As more steps have to take place for them to have their effect (they have to activate the G-protein, which in turn has to react with other stuff), their method of action is relatively slow compared to ion-channel receptors. However, in the whole scheme of things, they are considered to be fast-acting (within seconds).

Now for an example! Salbutamol is a beta 2-adrenoceptor agonist that relieves bronchospasm in asthma. Beta 2-adrenoceptors are G-coupled receptors that, when activated, release a stimulatory G protein (G_s) which activates adenylate cyclase. cAMP is then produced, resulting in relaxation of the airways.

Enzyme-linked receptors

Enzyme-linked receptors pretty much are enzymes. Like G-protein coupled receptors, they are located in the cell membrane, with their N-terminus extracellular and their C-terminus intracellular. Usually the N-terminus is where the signalling molecule binds, whereas the C-terminus is the enzyme part. They usually respond to hormones for growth and differentiation, and as such their effects are slower, normally in the time scale of minutes.

An example of a molecule that binds to an enzyme-linked receptor is insulin. Insulin binds to insulin receptors, which act as tyrosine kinases. The overall effect of these kinases is to translocate the glucose transporter GLUT4 to the cell membrane, so that glucose can enter the cell where it is needed for metabolism.

DNA-linked receptors

DNA-linked receptors act directly on DNA (again, as their name suggests... methinks these receptors won't be difficult to remember). They are the only receptors that are located intracellularly. DNA-linked receptors normally respond to hormones, particularly steroids. Their mechanism of action can take hours as genes have to be transcribed and proteins have to be produced.

An example here is glucocorticoid drugs such as cortisone. They are anti-inflammatory agents that have their effects by binding to DNA-linked receptors, which in turn bind to the DNA. (As for which genes they transcribe... I guess I'll have to find that out.)

Explain, with examples, how ion channels, enzymes and transporters are important drug targets.

I feel like I've already done this by talking about the receptors above, but they did provide some more examples in the lecture so let's go over those.

Ion channels

Some of the drugs that react with ion channels include blockers and modulators. Blockers physically plug the channel, preventing stuff from passing through. I've already given an example here with local anaesthetics blocking nicotinic ACh receptors (which are also Na⁺ channels). Modulators bind to other accessory sites on the channels, modulating their activity. An example here is benzodiazepines (e.g. Valium) which are sometimes prescribed for anxiety. They enhance the opening of GABA-activated Cl^- channels.

Enzymes

Once again, I feel like I've pretty much covered this in the enzyme-linked receptor section, so I'm just going to provide a few more interesting tidbits instead. Interesting tidbit number 1 involves substrate analogues, which are basically drugs that act as competitive inhibitors. Sometimes the enzyme might actually break them down, but an abnormal metabolite is produced. For example, fluorouracil, an anti-cancer drug, replaces uracil. It cannot be broken down to thymidylate (a component of DNA), so DNA synthesis is inhibited.

Transporters

Sometimes transporters are also targets for drugs. For example, SSRIs (selective serotonin reuptake inhibitors) selectively prevent serotonin from being transported back into a neuron, allowing it to hang around in the synapse for longer and continue to stimulate the postsynaptic neuron. False substrates can be an issue here as well- amphetamines can hijack the noradrenaline transporter and replace or release noradrenaline and serotonin.