Ligand Gated Ion Channels Flashcards
what are the members of the LGIC family?
- 5-HT3
- GABAa + GABAc
- glycine
- glutamate
where is nAChR located?
in periphery of NMJ
also found in CNS and spinal cord
what is nAChR composed of?
5 transmembrane segments
2 alpha, beta, gamma, delta
are encoded by 4 diff genes
the alpha polypeptide chains have …
binding sites for ACh
what happens when 2 ACh molecules bind?
induce conformational change that opens channel
channel stays open for 1msec
what are the 3 conformations of the ACh receptor?
- unoccupied + closed
- occupied + closed
- occupied + open
what do clusters of negatively charged amino acids at either end of the pore help exclude?
negative ions
encourages pos ions of less than 0.65nm diameter to pass through
what are the main ions that are able to pass through the pore?
Na+
K+
Ca2+
what does a large influx of Na+ cause?
membrane depolarisation + skeletal muscle contraction
what does prolonged contact of receptor with inc conc of ACh result in?
desensitisation of receptor
what is the location, structure and signal transduction mechanism of the Nm receptor?
skeletal neuromuscular junction
pentameric
Na+ depolarising ion channel
what is the location, structure and signal transduction mechanism of the Nn receptor?
post-synaptic cell bodies, dendrites
alpha and beta subunits only (as 2-alpha-3beta)
Na+ depolarising ion channel
what are most neuronal nAChRs composed of?
alpha and beta subunits in ratio 2:3
describe ligand-gated ion channel gating?
channels open/close in response to binding of signalling mol
e.g. ACh nicotinic receptors, GABAz receptors
describe voltage-gated ion channel gating?
allow influx of ions into cell
found in neurones/cells
what are the 3 subtypes of the GABA receptor?
- GABAa - ligand gated ion channel
- GABAb - G protein coupled receptors (exists as dimer)
- GABAc - ligand gated ion channel
what are the GABAa and GABAc receptors linked to?
chloride ion channel
how many subunits are there for the GABAa receptor?
there are 6 alpha, 3 beta and 3 gamma
in alpha2-beta2-gamma arrangement
give examples of agents that are able to bind to GABA?
- neurosteroids
- anticonvulsants
- barbiturates
- convulsant - picrotoxin
when GABA and BDZs act on their receptors, what do they do?
enhance binding of each other
BDZs cause conformational change - > modulates binding of GABA
GABA receptor changes from low affinity to high affinity
Cl- channel stays open
give an example of a GABA agonist?
THIP (gaboxadol)
give an example of a competitive agonist at GABAa?
bicuculline
give examples of non-competitive agonists at GABAa?
picrotoxinin
TBPS
what do GABA reuptake inhibitors do?
and also give an example of a reuptake inhibitor?
increase GABA levels at postsynaptic receptor
tiagabine (gabitril) -> derivative of nipecotic acid
is potent GABA reuptake inhibitor used as anticonvulsant
what are the uses of barbiturates?
- hypnotics - used for severe insomnia in patients ALREADY taking barbiturates
- sedatives
- anticonvulsants
- anaesthetics
what are the thiobarbiturates?
derivatives of barbiturates
contain sulphur mol in place of one oxygen mol
what is thiopentone used as?
intravenous anaesthetic
recovery = rapid
few side effects
what are the problems with barbiturates?
- patients develop tolerance
- habit forming
- therapeutic index = narrow
- therapeutic dose v close to fatal dose
- dangerous drugs -> used in suicide
- interacts with alcohol
give an example of BDZ receptor antagonist?
flumazenil
prevents binding to BDZ but not GABAa
what is flumazenil used for?
treatment of BDZ overdose
what are the uses of BDZs?
- hypnotics
- anxiolytics - short term relief of severe anxiety
what are the advantages of BDZs over barbiturates?
don’t directly open Cl- channels
not as lethal in overdose
what effect does alcohol have?
- effect on GABAa receptors - opens Cl- channel
- primary effect. in CNS as depressant
- at low doses = stimulatory
- inhib effects of ethanol suppress fear/anxiety
effects of ethanol
- chronic use -> changes in brain + behaviour
- enzyme responsible for metabolism = alcohol dehydrogenase
- response in neurones is diminished
what is the mechanism of action of alcohols?
- binds to multiple receptor sites on neurones
- dissolves in lipid bilayer of membranes -> inc fluidity
- binds to + enhances function of GABAa receptors
L-glutamate
- major excitatory neurotransmitter in CNS
- needed for normal brain function (lethal if too much)
- receptors play vital role in synaptic plasticity + higher cognitive function
- potential targets for therapies for CNS disorders
ionotropic receptor subtypes consist of 4 subunits + are subdivided into 3 groups based on agonist selectivity
what are they?
- NMDA (n methyl d-aspartate) receptors
- AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptors
- Kainic acid (KA) receptors
what are the functions of NMDA receptors?
- synaptic plasticity
- LTP (long term potentiation)
learning/memory
give the properties of NMDA properties?
- have high ca2+ permeability
- at single synapse - coexist with AMPA / kainate receptors
unlike most receptors, what must bind to the receptor complex with glutamate to activate the receptor?
second agonist (co-agonist - glycine)
NMDA receptors are tetrameric LGICs comprising…
- glycine binding GluN1 subunits
- glutamate binding GluN2A-2D + GluN3A-Bsubunits
NMDA receptors are implicated in diseases such as….
- ischaemia/stroke (excessive glutamate)
- parkinsons (pathways = overreactive)
- Huntington’s disease (disrupted ca2+ homeostasis –> excitotoxicity)
- neuropathic pain
AMPA receptors
- expressed in CNA
- tetramers of 4 subunits - GluA1-4
what are AMPAkines?
drugs that can be useful in treating psychiatric + neurological diseases
what do AMPAkines do?
help formation of LTP + can be used as memory enhancing drugs
upregulate neurotrophins e.g. BDNF
kainate receptors?
- more restricted distribution
- tetrameric combinations of 5 subunits - GluK1-5
- involved in presynaptic regulation of neurotransmitter release
- involved in excitatory imbalance - linked to epilepsy
