4 - Ligand gated ion channels Flashcards
What are the 3 essential functions of ion channels?
- Transport ions across the membrane
e.g. secretion/ absorption of fluids - Regulate membrane potentials
e.g. nerve and muscle cells - Ca2+ influx into the cytoplasm
e.g. secretion and muscle contraction
What are the main structural features of all ion channels?
transmembrane proteins are made up of 2 or more alpha-helices that cross the lipid bilayers
made up of 2-6 subunits - usually surround pore
How are ion channels classified into subgroups?
- Gating mechanism - voltage or ligand
- ion selectivity of the pore
defined by the physical size of ‘filter’ and aa lining the pore
what is an alpha helix?
a right hand helix conformation
What is a beta sheet?
beta strands connected laterally by at least 2 or 3 backbone H bonds
form a sheet
What is the P-loop?
the pocket where the ion will bind
Structure of a simple ion (K+) channel?
TM helicase forms p-loop - highly selective
2 helices span memb - surround pore
in cytoplasm TMs packed - create gate
when ions flow in - TMs move - allow potassium to pass through
What factors control the TM gate on the cytoplasmic side?
- membrane potential
- Mechanical stress
- ligands
What are the 2 main functions of voltage-gated ion channels
- Na+ and K+ create action potentials in excitable cells
- Ca2+ transported into the cytoplasm where 2nd messengers elicit a cellular response
How is the structure of a voltage gated channel different to a simple ion channel?
voltage gated channels have:
- additional helices S1 and S4 - form separate ‘voltage sensing domain’ lateral to subunits
- large polypeptides that extend to cytoplasm
- plugging mechanism
What are transient receptor potential channels?
Share common structural feaures w/ voltage gated channels
but have evolved to sense chemicals and physical stimuli
e.g. hot/spicy food
How are ligand binding ion channels different to voltage-gated?
are similar in structure but are controlled by the binding of a ligand
What are examples of ligand gated ion channels?
- calmodulin bound to c-terminal
- cyclic nucleotide-binding domain
What do Na+/ K+ selective channels control?
membrane excitability - they depolarise cells
What do calcium-permeable channels control?
regulate activity of calcium-sensitive proteins
What do chlorine selective channels control?
membrane excitability - reduce resistanc/ hyperpolarise cells
reduce action potential firing
What is the structure of a Cys-loop type receptor?
pentameric assembly
e.g. nicotinic assembly - nicotinic acetylcholine receptor
Neuronal nicotinic acetylcholine receptors and nicotine addiction:
neuronal nACHR exist as alpha 2-10 and beta 2-4
each have diff affinity depending on composition and location
Which neuronal nACHRs have a high affinity to nicotine and varenicline?
Alpha4 beta 2
are expressed in cortex and hippocampus
What does chronic exposure to nicotine lead to?
receptor upregulation
more receptors so more nicotine needed for same effect
specific polymorphisms in subunit genes CHRNA4 (alpha4) and CHRNA6 (alpha6) are linked to tobacco dependence
What causes autosomal dominant nocturnal front lobe epilepsy?
mutation in nACHR in M2 region of alpha4 nicotinic subunit cause ADNFLE
enhanced receptor function = increased nicotinic - mediated transmitter release = ADNFLE seizures
What is the main neurotransmitter in the brain?
glutamate
What is the structure of a glutamate receptor?
tetramer - similar structure to KcsA
except pore is inverted
form as dimer/ dimers
ligand binding site in cleft ‘closes’ when occupied
vital to brain fuction
What are the 3 main types of glutamate receptor?
AMPA
Kainate
NMDA
What do AMPA receptors do?
mediate fast excitatory synaptic transmission in the CNS
What do NMDA receptors do?
N-methyl-D-aspartate receptor -
involved in learning + memory
control synaptic plasticity
slower than other isoform
What do kainate receptors do?
similar to ampa
but lesser role of synapses linked to schizophrenia, Depression + huntingtons
What are the functional consequences of RNA splicing in AMPA receptor subunits?
alternative splicing = diff isoforms w/ diff functional properties
each subunit 2 isoforms - flip + flop
alternative splicing in 2 exons in primary transcript = 2 prot isoforms w/ diff domain in extracellular loop
different kinetic properties
What are the functional consequences of RNA editing in AMPA receptor subunits?
can result in aa substitutions - affect receptor functions
GluA2 Q/R site located in M2 of subunit - inside channel pore
mutation leads to CAG (glutamine) codon becoming CGG (arganine) codon
alters permeability + conductance
What is an example of dysfunction of glutamate NMDA receptors?
NMDA thought to be important for controlling synaptic plasticity + mediating learning and memory function
excess stimulation of NMDA - lead to neuron death
Dysfunctions of RNA modification can lead to pathological conditions example:
Downregulation of GluA2 Q/R editing in motor neurons of ALS patients = increase in Ca2+ permeability receptors
causes damage due to glutamate excitotoxicity
Structure of P2X receptors
trimeric assembly
e.g. Adenosine Triphosphate (ATP) gated ion channel
3 subunits w/ TM helicase
large extracellular domain
3 ATP molecules needed to open channel
widely expressed
P2X1-7 subtypes of subunits
