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how do drugs exert their action
by binding to proteins
4 classes of proteins targeted by drugs
ion channels, enzymes, ion channels receptors
what are ion channels
protein channels in the membrane that allow lipophobic /hydrophilic molecules through
which ion channels to drugs target
involved in neurotransmission
examples of drugs that target neurotransmission
sodium channel blockers
gabapentin
how does gabapentin work
targets voltage gated calcium ion channels to prevent its movement and prevent AP
role of receptor targeting
regulates cellular processes
enables communication between cells
enables coordination of tissue, organ and bodily responses
how do drugs causes side effects despite being targeted
off target effects can occur which occurs from interactions with receptors in multiple organs
what is an example of a drug and its side effects
opium has analgesic and euphoric effects but can cause constipation and respiratory diseases
how does opium use lead to addiction
activation of reward pathways and changes in receptor function (tolerance)
what is the cause of death in opium addicts
respiratory disease and suffer from chronic constipation
how do receptors help in drug function
allows for specificity in drug function
which type of receptor does not pass through the membrane
steroid
what do ionotropic, metabotropic and kinase linked receptors have in common
they are found on the cell surface and have transmembrane spanning segments of 20-25 hydrophobic amino acids
what is a feature and function of DNA linked receptors
regulates gene transcription
ligand must be able to cross the plasma membrane (lipophillic)
what is an example of a DNA linked receptor
oestrogen receptors
what is a ligand
any molecule that binds to the receptor
what is a Agonist
drugs or chemical mediators that bind to a receptor producing a response
examples of agonists
pilocarpine, nicotine, aCh, morphine
what is an antagonist
does not a cause a downstream response or prevents/ inhibits the response of an agonist e
examples of antagonists
atropine curare
how long is the signal transduction of ionotropic, metabotropic, kinase-linked and nuclear receptors
mms, s, hrs, hrs
what is an example of a LGIC
nicotinic ACh receptor
what is an example of a metabotropic receptor
Muscarinic ACh receptor
what is an example of a kinase-linked receptor
cytokine receptor
what is an endogenous receptor
a compound naturally produced by the body which binds and activates the receptor
what is the endogenous molecule for ionotropic receptors
small molecule chemical mediators not proteins
what happens when a molecule binds to an ionotropic receptor
central aqueous pore opens
how many transmembrane domains in GPCRS
7
what structure do GPCRs have
alpha helical structure
what is a heterotrimeric GTP binding protein
g protein
when do lignad gated ion channels open
when they are bound by an agonist
what does activation of an ionotropic receptor by excitatory neurotransmitters cause
membrane depolarisation and action potential firing
where are nicotinic acetylcholine receptors found?
neuromuscular junction, autonomic ganglion neuron, brain neurones
what is the agonist for NaChR
ACh and nicotine
what is the antagonist for NaChR
tubocurarine (curare)
examples of ionotropic glutamate receptors
AMPA and NMDA
what are the 2 most common receptors
ligand gates and G protein coupled
what are most hormones detected by
GPCRs
what is the structure of GPCRs
a single protein and spans the membrane 7 times
how do GPCRs work?
regulate effector proteins via heterotrimeric GTP binding protein
what is the structure of a g protein
1 alpha, 1 beta, 1 gamma (heterotrimeric)
how does signal transduction occur in GPCRs
via activation of g proteins
how are g proteins selective
they can be made up of 30 different alpha, beta and gamma units to make different g proteins which interact with different GPCRs and effectors
how many members of the GPCR family are there
800+
what do GPCRs respond to
hormones, inflammatory mediators and chemokines
why does GPCR signal transduction take longer than LGIC?
it is cascading and involves changing the function of different proteins
where is the ligand binding site in an opioid receptor
buried within the transmembrane receptors
what happens when the ligand is bound to a GPCR
it will make contact with several amino acids which influences the structure that the receptor will adapt
which effectors can g proteins control
ion channels, enzymes
types of ligand gated ion channels
cys-loop
ionotropic glutamate
P2x
calcium release
examples of cyc-loop type receptor & assembly
nAChR, GABAa 5HT3
pentameric
exmales of ionotropic glutamate type receptor and assembly
NMDA
tetrameric
example of P2X type receptor and assembly
P2XR
trimeric
examples of calcium release type receptor and assembly
IP3R, RyR
tetrameric
what are LGIC used for
fast synaptic transmission
what are the endogenous agonsists for LGIC
fast classical neurotransmitters stored in vesicles
what are LGIC composed of
3-5 subunits
how many transmembrane domains does each LGIC subunit have
2-5
when does a LGIC close
when the agonist is removed or the receptor enters a desensitised state
what causes changes in the excitability of a cell
ions flowing through open LGIC
what happens in the activation of ionotropic receptors for inhibitory neurotransmitters
membrane depolarisation is inhibited
action potential firing is reduced
what is an example of a receptor for an inhibitory neurotransmitter
GABAaRs expressed by the brain w
what is the agonist for GABAaRs
GABA, phenobarbitone
what is the antagonist for GABAaRs
Picrotoxin
what is phenobarbitone used for
epilepsy
what is the use of picrotoxin
CNS and respiratory system stimulant
what is myasthenia gravis
an autoimmune disease where the body creates antibodies to skeletal nicotinic acetylcholine receptors
what are the symptoms of myasthenia gravis
increasing muscle weakness, eye drooping
how many people suffer with myasthenia gravis
1 in 2000
how is myasthenia gravis treated
anti-cholinesterase to prevent the breakdown of ACh, and immunosuppressants
example of an anticholinesterase
neostigmine, pyridostigmine
why are some GPCRs referred to as orphans
because the ligand they respond to has not been identified
when does signal transduction occur
following an agonist binding to a GPCR and activation of a g protein
one G protein is used by _______ receptor
more than one
how do g proteins achieve signal transduction
by undergoing an enzymatic cycle
which g protein subunits interact with effectors
alpha and beta
what happens when the agonist is bound to the GPCR
it stabilises the helices and activates signalling
what happens when the antagonist is bound to the GPCR
it interacts differently with amino acids and adopts a shape not conducive to signalling
what happens after agonist binding to GPCRs
signal transduction via g proteins which control the function of effectors
how many types of g proteins are there
20
what are second messengers
small diffusible molecules that spread signals
how do noradrenaline and adrenaline work
via g protein coupled receptors
where is the binding site of the g protein
the alpha subunit