Session 7 Flashcards
How do ligand gated ion channels work?
Ligand binding ‘gates’ the channel to allow ions to move into or out of the cell (e.g Na+ in, K+ out)
What are the super families of cell-surface receptor?
Ligand-gated (receptor operated) ion channels
Receptors with intrinsic enzymatic activity
G protein coupled receptors
How do receptors with intrinsic enzymatic activity work?
Ligand binding activates an enzymes activity that phosphorylates the receptor itself and other substrates –> signalling scaffold leading to signalling cascade
How do G proteins-coupled receptors work?
Agonists - bind to receptor and activate it
Antagonists - bind to receptor but do not activate it
Give some examples of therapeutic application of drugs targeting GPCRs
CNS - depression, schizophrenia, psychosis, Parkinson’s, migraine
CVS - hypertension, congestive heart failure, cardia arrythmia
Respiratory - asthma, COPD
GI - acid reflux, gastric ulcer, nausea
Others - chronic pain, glaucoma, rhinitis, motion sickness, anaphylaxis
Broadly speaking what can GPCRs respond to?
Ions (H+, Ca2+)
Neurotransmitters (e.g. acetylcholine, glutamate)
Peptide & non-peptide hormones (e.g. glucagon, adrenaline)
Large glycoproteins (e.g. TSH)
What is the basic structure of GPCRs?
Single polypeptide chain (300-1200 aa), 7 transmembrane spanning regions, extracellular N-terminal, intracellular C-terminal
Which regions of GPCRs can be responsible for ligand binding?
Can be formed by 2/3 of the transmembrane domains
Can be the N-terminal region
How many subunits are there in GPCRs?
What are they called?
Three.
They are called, alpha, beta and gamma subunits
What is the significance of the GPCR-G protein interaction?
It activates the G protein by causing GTP to be exchanged for GDP on the G protein alpha subunit
What happens when a G protein is activated?
The alpha subunit dissociates from the beta-gamma complex. They then interact with effector proteins. These interactions last until the alpha subunit GTPase activity hydrolyses GTP to GDP, at which point the alpha subunit and the beta-gamma subunits then reform an inactive heteromeric complex.
What effect does nor/adrenaline have on GPCRs?
Effects beta-adrenoreceptor and Gs alpha. Effector = activation of adenylyl cyclase
Effects alpha2-adrenoreceptor and Gi alpha. Works to inhibit adenylyl cyclase
What effect does light have on GPCRs?
Acts on rhodopsin, Gt alpha and activates cyclic GMP phosphodiesterase
What effect does ACh have on GPCRs?
Acts on M2/M4 muscarinic receptors and Gi alpha. Works to inhibit adenylyl cyclase
Acts on M1/M3 receptors and Gq alpha. Works to activate phospholipase C
What effect does pertussis toxin have on GPCRs?
Pertussis toxin contains an enzyme (ADP-riobsyl transferase) activity which specifically modifies (and inactivates) Gi-type proteins, “uncoupling” receptor-effector linkage.
