2 - Ligand Gated Ion Channels Flashcards
What are ion channels?
- Transmembrane proteins that span the membrane from one end to the other.
- They are specific.
What are the main structural features of ion channels?
- 2 or more helices that cross the lipid bilayer.
- 2-6 subunits, that usually surround the pore.
What are ion channels classified based on?
Their gating mechanism and the ion selectivity of the pore.
What are some of the feature of a simple potassium ion channel?
- Transmembrane helicase structures form a p-loop structure.
- Forms a gate which is closed when in a resting state on the cytoplasmic side.
What do Na+ and K+ do in excitable cells?
Create action potentials.
What does Ca+ do after being transported into the cytoplasm?
causes a 2nd messenger to elicit a cellular response.
How are voltage gated ion channels different to ligand gated ion channels?
- They have additional helices, S1-4 form a separate voltage sensing domain that is lateral to the subunits.
- They have large polypeptides that extend into the cytoplasm.
- they have plugging mechanisms.
What are transient receptor potential (TRP) channels?
Channels similar to voltage gated channels but have developed to detect stimuli such as chilli.
What are ligand gated channels controlled by?
The binding of a ligand
What happens when calcium binds to calmodulin?
the channels close and it creates negative feedback
What are the categories of extracellular ligand gated ion channels?
Pentameric (Nicotinic) - 4 transmembrane domains, 5 subunits including the pore
Tetrameric (Glutamate) - 3 transmembrane domains, 4 subunits including the pore.
Trimeric (ATP P2X) - 2 transmembrane domains, 3 subunits including the pore.
Features of Pentameric Assembly (cys-loop type)
- Includes nicotinic acetylcholine receptors (nAchRs)
- Subunits can move to make more space for ions to move through the channel
- large external facing N domain and an intracellular loop between M3 and M4.
What no neuronal nAchRs exist as?
a2-10 and b2-4, each with different affinity depending on location and composition.
What is significant about a4 and a2?
- They are expressed abundantly in the hippocampus and the cortex with high affinity to nicotine and varenicline.
- Chronic expose to these chemical leads to upregulation of the receptors, which is linked to nicotine addiction.
What do mutations in nAchRs cause?
autosomal dominant nocturnal frontal lobe epilepsy. (ADNFLE)
How does enhanced receptor function cause ADNFLE seizures?
By increased nicotinic mediated transmitter release.
What is another cause of ADNFLE seizures?
Mutation in the M2 region of the a4 neuronal nicotinic subunit.
Features of Tetrameric Assembly (Glutamate receptors)
- Similar structure to KcsA except the pore is inverted.
- Forms as as dimer, the ligand binding sit closes when occupied.
- Vital to every aspect of brain function and dysfunction contributes to human diseases.
How does diversity in glutamate receptors come about?
From the difference in the way RNA is processed in the cell during RNA splicing.
What are the 2 isoforms of glutamate receptors (eg AMPAR)?
Flip and flop
What is the main difference between flip and flop?
Flop is faster in terms of desensitisation rate and reduced current response to glutamate.
What contributes to the diversity of glutamate receptors?
Multiple genes, splicing and mRNA editing.
What is the function of AMPA receptors?
Mediate fast excitatory synaptic transmission in the central nervous system.
What is the function of NMDA receptors?
They are involved in learning and memory, they are also slower than other isoforms.
What is the function of Kainate receptors?
Similar to AMPA receptors but have less of a role at synapses linked to schizophrenia, depression and huntingtons.
What does the dysfunction of RNA modification lead to?
pathologic conditions.
What does the downregulation of GluA2 Q/R editing in the neurons of ALS patients lead to?
An increase in Ca2+permealble AMPA receptors which causes damage due to glutamate excitotoxicity.
In glioblastoma what correlated with increased malignancy?
Decreased ADAR2 activity and in increase in Ca2+ pathway promoting proliferation and tumorigenesis this was reversed when GluA2 Q/R was edited.
