Receptor Physiology Flashcards
Classify receptors
- Ionotropic (channel-linked)
- Metabotropic (G-protein coupled)
- Enzyme (kinase)-linked
- Gene transcription linked nuclear receptors
Classify common Ionotropic (channel-linked) receptors. Give common examples
LIGAND GATED ION CHANNELS
- nicotnic Ach receptor
- GABA (type A receptor)
- NMDA receptor
- 5-HT3 receptor
VOLTAGE GATED ION CHANNELS
- Ca channels
- Na Channels
How to ionotropic ion channels work
Facilitate movement of ions down their concentration gradient
Passive
Rapid
What is the name of the enzyme and precursors that synthesize acetylcholine
What is the name of the enzyme that catabolises acetylcholine
Synthesis
- Choline acetyltransferase (precursors: Acetyl CoA + Choline)
Catabolism
- Acetylcholinesterase to choline and acetate
Describe the structure of the nicotinic Ach receptor
Pentameric ligand gated ion channel with 5 subunits including (clockwise from 12 o’clock)
- Alpha
- gamma (fetal) / Epsilon (adult)
- Delta
- Alpha
- Beta
Active binding sites of Ach are on the two alpha subunits
Describe the functions of the nicotinic receptors at the skeletal muscle NMJ in terms of the following:
- Postsynaptic nicotinic receptors
- Pre-synaptic nicotinic receptors
- Perijunctional nicotinic receptors
- Postsynaptic nicotinic receptors
- Initiate muscle contraction - Pre-synaptic nicotinic receptors
- Mobilization of additional Ach for pre-synaptic release - Perijunctional nicotinic receptors
- On perijunctional cells but not normally involved in NM transmission. But these receptors are upregulated with prolonged immobilization or following thermal burns
How are central Ach receptors affected by anaesthetic drugs
Barbiturates, Propofol and Volatile anaesthetic agents inhibit excitatory nicotinic Ach receptors in the CNS
What is the endogenous ligand for GABA type A receptor and how do anaesthetic agents influence this receptor
Engogenous ligand is gamma aminobutyric acid
Activity of GABA type A is enhanced by
- Barbiturates
- Propofol
- R-etomidate
- Volatile anaesthetic agents
- Benzodiazepines
- Glucocorticosteroids
Where is the benzo and volatile/propofol/etomidate/barbiturates binding sites on the GABA type A receptor
Pentameric ligand gated ion chanel (Cl- ionopore) 5 subunits (from 12 o'clock)
- Beta
- alpha
- Beta
- alpha
- Gamma
Benzo site - between alpha and gamma
All other GA bind to Beta subunit producing positive allosteric modulation
What is the NMDA receptor named after. What is the endogenous and exogenous ligands.
Which anaesthetic agents influence this receptors
N-methyl-D-aspartate exogenous ligand for this receptor
endogenous ligands
- Glutamate (excitatory)
- Glycine (inhibitory)
Ketamine and Magnesium block NMDA receptors
How does the 5HT3 receptor differ from the other 6 5HT receptors and which drugs act on this receptors
5HT3 receptor is an ion gated channel
All the other 5HT receptors are G-protein coupled receptors
Ondansetron and Granisetron act on this receptor.
Differentiate between the activated and inactivated seven serpentine transmembrane heterotrimeric G-protein coupled receptor
Activated
- -> Alpha subunit of G-protein is bound to GTP
- -> Beta and gamma subunits are detached
Inactive:
- -> Alpha subunit is bound to GDP
- -> Beta and gamma subunits are attached
Describe the mechanism of action of Gs, Gi and Gq proteins
Affects vary according to ligand and tissue site
Gs –> stimulate Adenylate Cyclase –> Increase IC cAMP –> + Protein Kinase A –> Variable effects but often increase IC Ca2+
Gi –> Inhibit Adenylate Cyclase –> Reduced cAMP
(Also activates phospholipase A2)
Gq –> stimulate Phospholipase C –> Increase IP 3 ( increase Ca2+ release ER) AND Increase DAG (Activates protein kinase C)
List Examples of the different Gs, Gi and Gq receptors
Gs
- B1, B2, B3
- D1
- H1, H2
- Glucagon
- ACTH, LH, FSH, VIP, GHRH, TRH
- Prostacyclin (PGI2)
Gi
- a 2
- M2 and M4
- 5-HT 1
- Opioid receptors
- GABA type B receptors
Gq
- a1
- M1, M3, M5
- 5-HT2
What breaks down cAMP
Selective PDE inhibitors
- PDEi 1,2,3,4,5,7,and 10
Methylxanthines
- Caffeine
- Aminophylline
- Theophylline
Why are muscarinic receptors so named
Muscarine is an alkaloid extracted from various mushrooms and mimics certain actions of Ach.
Where are M2 cholinergic receptors found and how do they work
Heart
- predominantly on the atria (some ventricular)
Gi protein mediated. Inhibition AC –> reduced cAMP –> negative inotropy (atria), chronotropy and dromotropy.
List and describe examples of enzyme (kinase) - linked receptors
- ANP
- -> Membrane bound receptor with intrinsic guanylyl cyclase activity –> increase cGMP IC –> phosphorylation of IC enzymes to mediate effects - NO
- -> Cytosolic guanylyl cyclase stimulated –> cGMP (rather than membrane bound) - Insulin
- -> Tyrosine kinase membrane receptor
- -> Ligand binds –> phosphorylation of the tyrosine residues –> activation tyrosine kinase –> phosphorylation of other protein targets –> many effects of insulin (insertion GLUT and gene transcription changes)
Describe the receptor binding mechanism for steroid and thyroid hormones
Traverse cell membrane –> bind to cytosolic cell receptors. Hormone-receptor complex is now permitted into the cell nucleus to act as a Ligand-regulated transcription factor.
The cytosolic proteins are normally held in an inactive form by other cytosolic inhibitory proteins.
Describe the two types of adrenosteroid receptors and where they are found
GR
MR
GR widespread
MR nephron and colon epithelial tissue.
Describe the mechanism of action of pioglitazone
Antidiabetic drug
Agonist at a nuclear receptor (Peroxisome Proliferator - activated receptor) –> controls protein transcription associated with increased sensitivity to insulin in adipose tissue
Describe the insulin receptor and how it works
- Enzyme linked receptor
- 2 alpha + 2 beta subunits (Heterotetramer)
- Alpha unit = ECF = binding site
- Beta unit = ICF + spans membrane + contains tyrosine kinase
Insulin binds alpha units –> brings beta units closer together –> mutual phosphorylation of tyrosine kinase + activation of tyrosine kinase which leads to:
- Activation transcription factors –> cell growth / division
- Protein synthesis / lipogenesis / glycogen formation
- Translocation GLUT 4 to cell membrane to increase glucose uptake (from cytosolic vesicle)
