Receptor Mechanism I Flashcards
The structural features of a LGICR
Nicotinic acetylcholine receptor has 4 transmembrane domains.
• The amino terminus of the protein, which goes in and out of the membrane 4 times.
• Transmembrane domain – amino acids in a long chain, of which some are hydrophilic and some hydrophobic.
• If proteins in plasma membrane are hydrophobic, amino acids would be in lipid phase.
• Clumps of hydrophobic amino acids are found in the phospholipid bilayer.
• Protein comes out into cytoplasm for hydrophilic amino acids, then carries into the second round of hydrophobic amino acids, etc.
Functional LGICR – made up of 5 similar proteins.
Total transmembrane domains= 5 similar proteins x 4 transmembrane domains = 20
- Second transmembrane domains, of each protein, clump together forming a cavity
- This cavity forms the ionic pathway, making the aqueous pore.
- Functional receptor has large external head, and a narrow region of amino acids, that determine which ion moves through the cell.
- 5 proteins coming together to create barrel-like structure for ions to flow
- Each functional protein is a pentamer
The mechanism that LGICRs produce a rapid cellular response.
As an agonist (drug) binds to receptor, it causes a conformational change which results in the instant movement of ions through the membrane
• Nicotinic Acetylcholine receptor – 2 alphas, where acetylcholine binds.
• To get activation of receptor – need 2 molecules of acetylcholine.
• Each protein has 4 transmembrane domains, each functional receptor has 5 similar proteins coming together, and each functional receptor needs 2 molecules of agonists to have an effect.
• As soon as acetylcholine binds, space in middle gets bigger.
• Channel opens allowing flow of ions set up by their ionic gradients - Na+ or Ca2+.
Discuss the key features of the neuromuscular junction and the role of nicotinic acetylcholine receptors.
4 agonists involved in LGICR superfamily.
• Nicotinic Cholinoceptor – activated by acetylcholine
• 5HT3 – activated by 5-HT
Activation using these agonists, causes Na+/Ca2+ ions to move across channel. The membrane potential becomes less negative – depolarisation occurs.
• GABAA – activated by y (gamma) amino butyric acid (GABA)
• Glycine – activated by Glycine
Activation using these agonists, causes Cl- ions to move across channel.
The accumulation of these ions makes the membrane potential becomes more negative – hyperpolarisation occurs.
These compounds are major inhibitory neurotransmitters in our brains.
Identify the molecular mechanisms underlying myaesthesia gravis and the potential treatments.
• Autoimmune disease which links to muscle weakness, fatigue… exertion is difficult
• Targets the a1 subunit (highly specific), where the protein becomes degraded by the immune defence system.
• The number of nicotinic ACh receptors becomes less, and so the number of nicotinic Ach in skeletal muscle to respond to ACh decreases.
• However, the neuronal nicotinic AChR’s are unaffected as it consists of a2-a8 subunits.
Normal
• Stimulate motor nerve – very little electrical responses and little EJP.
• If zoom into the nerve of a normal person, the resting membrane potential has little depolarisation (fluctuations) called miniature end-plate potentials (mepps)
• ACh vesicles randomly colliding with the membrane – and so depolarisations always occur.
Myaesthesia gravis
• Muscles of diseased – little mepps, not because no random Ach, but because there isn’t the AChR there to receive the signal.
Fast inhibitory transmission in the central nervous system
-• Brain – neurones that synthesise GABAA.
• These inhibitory neurones, release GABA onto other neurones which have GABAA receptors
• GABAA receptors made of 5 similar proteins.
• As soon as GABA or glycine binds to these receptors
• We need two molecules of GABA to bind
• Total transmembrane domains in receptor – 20
- Unlike nicotinic AChR, where as soon as agonist binds – get cation influx
- Now, get chloride response
4 main types of receptors
- Ligand Gated Ion Channel Receptors (acetylcholine, glutamate, glycine)
- G-protein coupled (Adrenaline, dopamine, acetylcholine)
- Tyrosine kinase linked (insulin, growth factor)
- Nuclear Receptors (steroids, vitamins)
Receptors can cause…
• Changes in DNA Transcription, • Alterations in ion channels, • Alterations in enzyme activity • Direct opening of an ion channel. Fastest change is those where the protein creates an ion channel and aqueous pathway
Inhibitory response
- Binds to pentamer receptor – influx of chloride ions.
- Things like Valium etc. - Bind to one of five proteins and stabilise open configuration so more chloride influx and more hyperpolarisation – boost level of activity
Sensitivity of a person to benzodiazepine is dictated by which gamma subunit it has in GABA receptor
The difference in sensitivity can be 10000-fold difference.
Structure of GABAA receptor has same functional consequences but pharmacological sensitivity is huge.
2 Subtypes of nicotinic acetylcholine receptor
• N1 or NM – muscular found in neuromuscular junction in skeletal muscle.
• N2 or NN - CNS or autonomic ganglia
Stimulation of nicotinic AChR in skeletal muscle contracts muscle quickly
• Acetyl choline is made in neurone and is stored in vesicles.
• Expression of nicotinic acetylcholine receptors on skeletal muscles cells isn’t all over skeletal muscle, but is concentrated in active zone opposite the nerve.
• If something blocked sodium channel, won’t give action potential which is important for muscle contractions.
At rest.. v. Stimulation
At rest
• No acetylcholine being released, and membrane potential is about -70mV
Stimulation
• Activation of the motor nerve, there is the release of acetylcholine, which will diffuse a short distance and interact with nicotinic acetylcholine receptors.
• 2 molecules of ACh binds to receptor, quickly, the channel opens, there’s an influx of cations into cell, which depolarises the membrane (less negative).
• This is known as a EJP (excitatory junction potential). This is enough to open voltage gated Na+ channels.
• Acetyl choline diffuses rapidly and is broken down by acetylcholinesterase.
• As soon as unbinds, LGICR shuts down and cell handles the sodium.
Receptors made up of 5 proteins with different compositions depending on; where in body, development or disease.
E.g.)
Embryonic AChR activated stays open longer – not brief influxes and brief contractions. As we use muscles more, undergo developmental change, changing proteins found in neuromuscular junction.
