L5 - basic concepts in neuropharmacology Flashcards
what affects the fraction of receptors in the R* state
drugs
receptor with constitutive activity
no ligand bound but equilibrium lies more towards activated state
non-zero baseline on graph
shows receptor with constitutive activity
agonist ligand - greater affinity for…
R* state (activated)
full receptor agonists reach
receptor saturation
inverse agonist
equilibrium held towards R state
antagonist ligand
prevents ligand binding therefore no downstream signalling
reversible or irreversible
reversible antagonist ligand
competes for agonist binding site
reversible binding
irreversible antagonist ligand
change conformation of receptor
reduces ability of agonist to bind
strong covalent bond - remains bonded until internal recycling
affinity
how well a drug binds to its receptor
efficacy
how well a receptor-bound drug elicits a response
potency
amount of drug required to elicit a response
allosteric modulators
impact receptor function by binding at an alternative receptor site
2 binding sites
orthosteric (enogenous)
allosteric site
how do you change the affinity of the orthosteric ligand
elicit conformational change of receptor so drug binds more/less easily
positive allosteric modulation
binding of ligand to receptor enhances signalling
when you change the efficacy of the orthosteric ligand
binding is unaffected
downstream signalling is affected (potential larger maximal response)
neurotransmitter
biochemical that mediates fast-acting direct communication between two neurons
neuromodulator
biochemical that modulates activity of neurons and neural networks by changing the ability of neurons to respond to neurotransmitters
examples of amino acid neurotransmitters
glutamate
gaba
glycine
aspartate
exmaples of biogenic amine neurotransmitters
ACh
histamines
monoamines
types of monoamine neurotransmitters
serotonin
catecholamines (dopamine, adrenaline, noradrenaline)
how does nitric oxide signalling modulate neurotransmission
Ca2+ influx downstream of ion channel
causes activation of nNOS
increased intracellular NO concentration
nNOS
neuronal Nitric Oxide Synthase
glial cells release transmitters that modulate neurotransmission
gliotransmitters
neurotransmitters
ionotropic receptors
ligand gated ion channels
transmembrane
mediate fast-transmission (open quickly)
examples of ionotropic receptors
nicotinic ACh R
5-GT
glycine receptors
ionotropic glutamate receptors
NMDA
AMPA
Kainate
NMDA receptor
ionotropic glutamate receptor with Mg2+ block
glycine is an +ve allosteric modulator to…..
NMDA
metabotropic receptors
couple via 2nd messengers
GPCR, RTK
indirectly open ion channels
2nd fastest
when ligand binds to RTKs
transautophosphorylation at Tyr residues
SH2 domains recruited
cytokine receptors
-ve feedback
bind to cytokines and transduce their signals
cytokines are neuromodulators
slower transmission
put the receptors in order of speed of transmission
x4
ionotropic
metabotropic
cytokine
hormone
hormone receptors
e.g. glucocorticoid/oestrogen receptor
when does receptor desensitisation occur
x2
at high levels of agonist exposure
due to chronic exposure to agonist ligand
mechanisms causing reduced response to ligand binding to receptor (receptor desensitisation)
x3
uncoupling
receptor internalisation
reduced receptor expression
receptor desensitisation can lead to….
drug tolerance
arrestins effect on GPCRs
proteins that mediate homologous desensitisation of GPCRs
cause uncoupling and receptor internalisation
tachyphylaxis
acute sudden decrease in response to drug after administration
tolerance
decreased response to drug after chronic use
addiction
behavioural manifestation of tolerance
