Lec2: Drug Targets Flashcards
Drugs act by binding to what molecule and inducing what kind of change? What is the exception to this standard?
Binds to proteins, and induces conformational change. Exception is binding to DNA –> antimours and antimicrobial drugs.
Cholinergic receptors respond to what neurotransmitter?
Acetylcholine.
What is acetylcholine synthesised? (2 sites of action and their respective mediators!) Also indicate the rate-limiting step.
- Choline uptake by secondary active transporters (mediated by transporters). –> Rate limiting step.
- Conversion of choline into acetyl choline by Choline Acetyl Transferase (mediated by enzyme).
Write the equation for acetylcholine synthesis.
Choline + Acetyl CoA —(ChAT)—> Acetylcholine + HSCoA
What are the four steps in the release of Acetylcholine into the synaptic cleft?
- Packaged in vesicles held by Ca2+ sensitive vesicle membrane proteins.
- AP arrives.
- Voltage dependent Ca2+ channels open
- Ca2+ influx stimulates vesicular fusion and therefore NT release.
Write the three basic steps in how receptors operate?
- Protein recognises specific NT
- Conformation change
- Activate or inhibit CELL SIGNALLING
What are the 4 families of receptors, and which are slowest and fastest acting?
- Ligand-gated ion channels (ionotropic) –> fastest
- G-protein coupled receptors
- Tyrosine kinase/Cytokine receptors
- Nuclear/Steroid hormone receptors –> slowest
How fast is a typical transmission by a ligand gated ion channel?
Less than 1ms
Are ligand gated ion channels multi-subunit or 1 subunit?
Oligomeric (multisubunit).
What are the 3 properties of ligand gated ion channels?
- Selective for difference ions
- Conduct ions through otherwise impermeable cell membrane
- Respond to specific ligands
Nicotinic acetylcholine receptors have how many subunits containing how many transmembrane domains each?
5 subunits with 4 TM domains each, therefore 20 overall.
What is the acetylcholine binding site on a nicotinic acetylcholine receptor composed of?
3 peptide loops on one subunit and 2 peptide loops on a neighbouring subunit.
In order for the channel in a nicotinic acetylcholine receptor to open, where must acetylcholine bind?
Two ACh must bind to the ACh binding sites, located between each of the two ALPHA subunits and a neighbouring subunit.
Describe the structure of receptor pore of nACh receptors. Also, what happens if there is a mutation to one of the critical TM2 residues?
- M2 helices form inwards constriction, but snap open when ACh binds.
- TM2 amino acids are highly selective for cations, but when a mutation is induced, they are made selective for anions instead. Therefore, no longer excitatory.
Describe, basically, the GPCR cell-signalling pathway.
- Ligand bind to receptors
- Activates G protein
- G protein activates adenylate cyclase
- Adenylate cyclase converts ATP to cAMP
- cAMP activates Protein Kinase A