ligand-gated channels Flashcards
functions of all ion channels:
transport ions across membrane
regulate membrane potentials
Ca2+ influx into cytoplasm
structural features of ion channels
- Transmembrane proteins made up of two or more ⍺-helices that cross the lipid bilayer
- Made up of two – six subunits which usually surround the ‘pore’
subgroups of ion channels
- Gating mechanism – voltage or ligand
- ion selectivity of pore
what are alpha helices
a right hand-helix conformation
what are beta sheets
Beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a sheet.
what are subunits
single protein that forms with others to form protein complex
what are transmembrane domains
protein that spans the width of the membrane from the extracellular to intracellular sides usually a helical shape
what are pores/p-loops
pocket where ion will bind
how many human genes code for membrane channels
400
primordal channel structure
- two transmembrane domains
- 3 subunits
- each subunit has two domains which surround the pore
- basic structure of all ion channels
potassium channel structure
- 4 subunits
- gene duplication → 4 transmembrane domains and 2 p loops
- single amino acid in one of the domains that allows recognition of k instead of all ions
- transmembrane helicase structures from p loop → highly selective
- cytoplasmic side = TM are more tightly packed = gate
sodium/ calcium channels structure
- 6 domains duplicated
- 24 domains
- 4 subunits that make up domains
ligand gated channel
6 transmembrane domains that surround a p loop
K channel gates are controlled by
- membrane potential
- mechanical stress
- ligand binding to C terminal
functions of V gated ion channels
- Na/K action in excitable cells
- Ca2+ transport into cytoplasm for 2nd messengers to elicit response
structural differences between V gated ion channels and simple ion channels:
- additional helices s1 and s4 form separate voltage sensing domain lateral to subunits
- large polypeptides extend into cytoplasm
- plugging mechanism - feedback mechanism
what are transient receptor potential channels (TRP)
have common structural features with V-gated channels but evolved to sense chemicals and physical stimuli
how do ligand-gated ion channels work
- Controlled by binding of ligand e.g cyclic nucleotide-binding domain
- Cyclic nucleotide binding domain on intracellular C terminal domain opens a pore permeable to Na+ and Ca+
- Ligand binds to 3/4 sites to open = sharp conc response curve
- channels either sense cAMP or cGMP
no subunits in simple, V gated, TRP and ligand gated channels
2
4
4
4
no TM helices in simple, V gated, TRP and ligand gated channels
2
6-24
6
6
are simple, V gated, TRP and ligand gated channels gated?
no
yes (changes in memb pot)
yes
yes (chem transmitters)
do simple, V gated, TRP and ligand gated channels have a p loop?
YES ALL
do simple, V gated, TRP and ligand gated channels have cytoplasmic anchors?
no
yes
yes
yes
do simple, V gated, TRP and ligand gated channels have voltage sensing domains?
no
yes - v gated
no
no
do simple, V gated, TRP and ligand gated channels have a plugging mechanism?
no
yes - v gated
yes - TRP
no
functional examples of simple, V gated, TRP and ligand gated channels?
simple = secretion/absorption of fluids
v gated = excitable cells
TRP = hot/spicy taste
ligand-gated = olfaction
families of ionotropic receptors:
ATP P2X
glutamate
nicotinic
do subunits in the brain vary with location?
Different subunit combinations make up receptors in different parts of the brain
pentameric receptors structure
- 4 domains
- EC domain recognises transmitters
- 5 subunits make up e.g nicotinic acetylcholine receptors
tetrameric receptors structure
- EC ligand binding site
- 3 domains
trimeric receptor structure
- 2 domains
- binding site for ATP in EC domain
- TM regulates specificity of channels
cys-loop type receptor - nicotinic acetylcholine receptor structure
- in muscle
- 5 subunits
- 4 TMs (M1-4)
- large external facing N domain and intracellular loop between M3 and M4
- M2 lines pore
targeting nicotinic receptors for nicotine addiction
- nAChRs exist as α2 - 10 & β2
- α4β2 are abundantly expressed in the cortex and hippocampus = high affinity to agonists nicotine and varenicline
- chronic exposure leads to receptor upregulation
mutation in nAChR and autosomal dominant nocturnal frontal lobe epilepsy
- Mutations in the M2 region of the human α4 neuronal nicotinic subunit cause ADNFLE
- Enhanced receptor function = increased nicotinic-mediated transmitter release = ADNFLE seizures
glutamate receptors structure
- tetramer with similar structure to KcsA except pore is inverted
- form as dimer of dimers, ligand binding site is in cleft that closes when occupied
- vital to brain function
AMPA receptorsfunction
mediate fast excitatory synaptic transmission in the central nervous system
NMDA = N-methyl-D-aspartatereceptor function
- involved in learning and memory
- slower than other isoforms
Kainate receptor function
- similar to AMPA but lesser role at synapses
- linked to Schizophrenia, depression and Huntingtons
functional consequences of RNA processing in AMPA receptor subunits
RNA splicing
- Each subunit exists as two splicing isoforms - flip & flop
- different kinetic properties e.g flop = faster desensitization rate and reduced current responses to glutamate than flip
RNA editing
- The GluA2 Q/R site is located in the M2 of the subunit, inside the channel pore
- CAG (glutamine) codon to a CGG (arginine) codon
dysfunction of glutamate receptors
- important for controlling synaptic plasticityand mediating learning and memoryfunctions
- Excess stimulation of NMDA in stroke leads to neuron death
dysfunction of RNA modifications → ALS
e.g downregulation of GluA2 Q/R editing in motor neurones of ALS patients
- increase in Ca2+ permeable AMPA receptors causes damage due to glutamate excitotoxicity
dysfunction of RNA modifications → glioblastoma
decreased ADAR2 activity correlated with increased malignancy
Increase in Ca2+ = Akt pathway promoting proliferation and tumourigenesis
P2X receptors structure
- ATP gated ion channel
- 3 subunits (trimeric)
- 2 TM helices
- large extracellular domain
- 3 ATP molecules needed to open
- widely expressed
- P2X1-7 subtypes of subunits
pathological conditions associated with P2X/trimeric
hearing loss
pain
inflammation
neurodegen disease
pathological conditions associated with glutamate/tetrameric
excess NMDA in stroke -> death
pathological conditions associated with cys-loop/pentameric
epilepsy
The selectivity for specific ions is determined by
the structure of the filter and amino acids lining the pore
function of an ion channel is largely determined by its
ion selectivity and gating mechanism
Gating of ion channels is regulated by
voltage or ligand binding
Diversity and specificity of receptors are useful because
they provide targets for drugs/inhibitors that can aid in the treatment of human conditions
