L7: Receptors as drug targets Flashcards
how can receptors be classified?
Pharmacology – selectivity of drugs
Agonist potency orders – not very useful (as agonists, affinities, potencies are very variable. Different ec50s and potencies etc. what they bind to)
Antagonist binding (KB)
Antagonist shifts in dose-response curves (pA2 Schild plots)
Function – what they do
Open ion channels
Activate G-proteins
Activate enzymes
Interact with DNA
Structure – what they look like
Proteins
Amino acid/nucleotide sequence
receptor subfamilies?
Ion channel receptors
Pentameric
Tetrameric
Trimeric
G-protein coupled receptors
Class A
Class B
Class C
Etc
Intrinsic enzyme receptors
Tyrosine kinase receptors
Particulate guanylyl cyclase
DNA binding receptors
ion channel receptors?
Also called
Ionotropic
Ligand gated ion channels
Receptor operated ion channels
All have agonists activate receptor??
Select group
GABA small A Glutamate (ionotropic)
Glycine
Nicotinic acetylcholine ATP(P2X)
Serotonin (5-HT3)
ZAC
Nicotinic acetyl choline family? Another subgroup with glutamate receptors. Ionotropic. And atp activated ion channels? P2x
pentameric ion channels?
cation: NA, CA, K
depolarises
nAChR
5-HT
ZAC
anion: Cl-
hyperpolarises
GABA small A
Glycine
5 subunits come together in the membrane.
4 alpha helices within 1 subunit within transmembrane?
Ligand binding on n terminus and c terminus on same side as n as even number ??? if odd then would be on other side
2nd transmembrane domain alpha helix thought to be the pore. Amino acid sequence in this region dictates which ions can bind. For cations: na, ca, k the nitoctinic acetyl cholrine receptor, 5-ht and zac. When agonist activates this it allows na out? and k and some ca in.
Positive ions flowing in cause depolarisation so excited.
Anion channels: cl-. Gaba and glycine are activated. Causes hyperpolarisation of the cell.
So thats what the pore region does.
Binding site in extracellular environment so suggests ligands are polar or charged as cant cross the membrane.
tetrameric ion channels?
ionotropic glutamare receptors
NMDA, AMPA and kainate receptors
cations: NA, KA and some CA
depolarises, excitatory
Glutamate receptors are ionotropic (meaning they are ligand-gated ion channels), unlike metabotropic receptors (which work via G-proteins).
Subunits and Structure:
Ionotropic glutamate receptors typically have 4 subunits that form the ion channel. Each subunit spans the membrane several times.
Inverted Helix ??/ idk what forms the pore.
The N-terminus (the part of the protein that is often involved in ligand binding) is on the extracellular side of the receptor, while the C-terminus is on the cytoplasmic side, despite the receptor having an odd number of transmembrane domains. This results in a more complicated binding site.
Functional Families:
Ionotropic glutamate receptors are classified into three main functional families based on their agonists (substances that activate the receptor):
NMDA Receptors (N-methyl-D-aspartate receptors)
AMPA Receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors)
Kainate Receptors (activated by kainic acid)
Ion Permeability:
These receptors typically allow the flow of sodium (Na+) ions into the cell and potassium (K+) ions out of the cell.
NMDA receptors are unique in that they also allow calcium (Ca2+) ions to enter the cell, which plays a role in various cellular processes such as synaptic plasticity (important for learning and memory).
Depolarization and Excitation:
The influx of positively charged ions (especially sodium and calcium) causes depolarization, which makes the inside of the neuron less negative and more likely to fire an action potential. This results in excitation of the neuron.
Most Important Excitatory Receptors in the CNS:
Glutamate receptors, particularly NMDA, AMPA, and Kainate receptors, are the most important excitatory receptors in the central nervous system (CNS). They mediate most of the fast excitatory signaling in the brain and spinal cord.
trimeric ion channels and what do these receptors have in common?
3 subunits come together in membrane. Transmembrane domain. Cationic channels. Na in k out ca in. depolisarion and excitatory. Ligand binding site not at n terminus as inside celll. C terminus inside. Ligand binding site in extracellular loop.
All have common: all have extracellular binding site, tell you if cannot cross pm, all have ™ domains to hold in membrane and have region that dictates which ions come.
If ptentameric- 4 ™ domains.
Tetrameric- 3 ™ domains
Trtimeric- 2 ™ domains
GPCR?
Also called
Metabotropic- modify metabolism inside the cell
Seven membrane spanning
Most common receptors.
1200 genes (3-4% human genome)
67% odorant receptors - receptors involved in smell or taste
Of 375 about 300 have an identified ligand - receptors we thinka re associated with endogenous agonist hormone? About 300 identified with ligand.
About 100 “orphan” receptors in 2005 (2022 = 57) ─µ
Orphan receptors- dont know ligand?
Subfamilies of GPCRs?
CLASS A
rhodopsin-like: adrenoreceptors, dopamine, muscarinic ach, serotonin (except 3), cannabinoid, histamine, neuropeptide, opsins etc.
CLASS B
secretin like: secrin, calcitonin, glucagon
CLASS C
mGlutamate-like
mGluRs
GABA (SMALL B)
calcium sensing
other subfamilies: D and F
