Biological Signalling Molecules Flashcards
Define physiology.
The close control of flow, and interplay of work and information.
Outline the solubility, plasma half-life, time course of its action, receptor location and mechanism of action for:
- Catecholamines.
- Peptide/ protein hormones.
- Steroid hormones.
Give a neurotransmitter example and the signalling function of acetylcholine, monoamines and amino acids.
Define the terms ligand, agonist and antagonist.
A ligand is a molecule that specifically binds to a target/ receptor.
An agonist is a molecule that activates a target/ receptor.
An antagonist is a molecule that blocks or inhibits a target/ receptor.
What are the 4 different drug targets?
RITE-K(L)ING.
Receptors, of which there are 4 subcategories.
Ion channels - voltage gated ions channels.
Transporters.
Enzyme.
Subcategories of receptors:
Kinase-linked receptors.
Ligand-gated ion channels.
Nuclear/ intrinsic receptors.
G-protein coupled receptors.
Outline what VGICs are and how they are affected by drugs.
They are integral membrane proteins that can be in open, inactive or closed states, based on membrane potential.
They can facilitate the movement of Na+, K+, Cl- or Ca2+ ions.
They can be modulated by drugs allosteric phosphorylation, causing a conformational change.
The can also have their pore blocked by the binding of a molecule.
Outline 3 conditions where VGSC would be the target.
Epilepsy - drugs that bind to the pore of the channel, blocking the flow of Na+ ions in depolarised/ inactivated states. This would inhibit a sodium influx and so slows the action potential, allowing normal levels of CNS activity.
Local anaesthetic - optimally blocks the pore in the inactive state, through the hydrophobic mechanism, preventing an influx of sodium.
Chronic pain - selectively blocks the pain signals, which is facilitated by blocking the VGSCs.
Outline how VGCC are a drug target.
Most of the drugs that affect VGCCs are blockers.
When a drug, such as amlodopine, binds to the pore of the VGCC, it inhibits the movement of calcium into the cell.
The reduced calcium influx prevents more calcium form the sarcoplasmic reticulum, of muscle cells, being released.
This, in cardiac muscle, prevents the binding to troponin-C, thus there is no conformational change of the tropomyosin and so there is not actin binding site for the myosin heads to bind to.
This prevents contraction, making the demand for oxygen for the heart to decrease, making it a good treatment for heart failure.
Outline how the transporters are a good target for treating depression.
Serotonin (5HT) is a neurotransmitter linked to mood.
When there is low concentrations of 5HT in the synapse, then there is a link to depression.
This means that by blocking the re-uptake of 5HT from the synapse, the concentration there will increase.
The selective serotonin re-uptake inhibitors inhibit the Na+/ 5HT co-transporter, through competitive or non-competitive inhibition.
This means that there is a reduction in the uptake of 5HT and so the patient doesn’t experience as many symptoms of depression.
Outline how the transporters are a good target for treating diabetes.
SGLT2 inhibitors are good for treating diabetes.
This is because SGLT2 co-transporters reabsorb sodium and glucose from the proximal convoluted tubule of the kidney.
By blocking this, through allosteric inhibition, more sodium and glucose is excreted in the urine, decreasing the plasma-glucose levels.
They are either given alone or in combination, usually with metformin.
Outline the two methods of targeting enzymes with drugs.
Directly - drugs acting as competitive/ non-competitive inhibitors, at the binding sites and a site other than this (allosteric), respectively.
Indirectly - targeting receptors to increase or decrease activity; kinases phosphorylate, nuclear receptors up/ down-regulate, etc.
Give an example of a drug that targets enzymes.
ACE-inhibitors.
Prevent the conversion of angiotensin I to angiotensin II.
This means that there is less sodium (thus, water) reabsorption, less stimulation to increase aldosterone secretion, and less vasoconstriction stimulation.
The decreases blood volume and pressure, which is effective for treating hypertension, and heart failure.
Outline the two sites at which receptor kinases, specifically tyrosine kinases, can be targeted by drugs, and what they can be used for.
The signal binding domain - this is outside the cell, and prevents the activation of the RTK (receptor tyrosine kinase).
The RTK catalytic domain - this is inside the cell, and prevents the auto-phosphorylation of the two domains.
By inhibiting the RTK, it prevents growth factors from binding to the receptors and initiating cell division. This means that it can be used in anti-cancer drugs.
As they are an insulin receptor, it can be used to help treat diabetes mellitus.
Outline the transduction steps of tyrosine kinase receptors with insulin.
1) Insulin binds to the signal binding site on the outside of the cell.
2) 2 insulin molecules are required to activate each of the 2 integral membrane proteins.
3) The monomers, once activated, form a dimer.
4) Each of the monomers will then auto-phosphorylate the tyrosine residues on the other monomer.
5) The RTK is then fully activated.
Outline the 3 ligands for tyrosine kinase receptors.
Peptides and proteins.
Hormones - insulin.
Growth factors and cytokines.
Outline the phosphorylation cascade of tyrosine kinases.
The binding of one or two ligands to the signal binding domains provides a large conformational change to occur.
Complete the table and state where the majority of the different types of LGICs are located within the body.
nAChR’s are abundant in the CNS and PNS.
GABAa (GABAb is a GPCR) is mostly found in the CNS, inhibiting excitatory inputs.
Glutamate is mainly an excitatory neurotransmitter in the CNS and sensory cells.
Glycine is primarily an inhibitory neurotransmitter in the brainstem and spinal cord.
Describe how nuclear receptors are activated.
A ligand binds to the ligand binding domain, stimulating a conformational change.
This conformation change allows the receptor to bind to the DNA at the hormone response element.
This binding causes the release of an inhibitory protein.
This can then regulate gene transcription, causing a cellular response in hours to days, due to the increase or decrease in protein synthesis.
