Receptors Flashcards
what are the three key sort of functions of ion channels?
- transport ions across the membrane
- allow Ca2+ influx for muscle contraction
- maintain membrane potentials
what are some common structural features of ion channels?
Alpha (⍺) helices - a right hand-helix conformation
Beta (β) sheets - strands connected laterally by at least two or three backbone hydrogen bonds, forming a sheet.
Subunits – single protein that forms with others to form protein complex
Transmembrane domain (TM) – protein that spans the width of the membrane from the extracellular to intracellular sides usually a helical shape
P-loop or pore – pocket where ion will bind
how are ion channels classified?
what is the earliest ion channel?
Classified by gating mechanism and ion selectivity (dependent on size and the Aa.s lining the pore)
All channels are evolved from pH-regulated K+ channel KcsA from bacterium streptomyces lividans
all ion channels have… (x2)
Transmembrane proteins typically with 2+ alpha helices
2-6 subunits (proteins combining to form the protein complex) surrounding the pore
explain the structure of a K+ channel (and the kind of ion channel it is)
its a simple ion channel -
2 Transmembrane domains, more tight on the cytosolic side of the bilayer (like a V) to form the ‘gate’ (but simple ion channels don’t have to be gated)
K+ must lose its water molecule to fit through (example of channel size contributing to selectivity)
Gate can be controlled by membrane potential, mechanical stress or ligands
what are the two main functions of voltage gated ion channels?
- Used to create action potentials via Na+ and K+
- Ca2+ influx for contraction
what structural features do voltage-gated ion channels have?
Additional S1 and S4 domains - detect voltage
Large polypeptides that extend into the cytoplasm - important for regulation of the channel
Plugging mechanism - literally a string of amino acid that blocks the pore when signalled to do so
what are transient receptor potential channels?
like voltage gated ion channels but they respond to chemicals and physical stimuli
for example TRPV responds to heat and capsaicin - spicy foods
give an example of an intracellular ligand-gated ion channel with detail on how it works
nucleotide gated channel -
C terminus has binding site for the cyclic nucleotide which opens gate (intracellular ligand)
N terminus (intracellular) has site for calmodulin to bind when there is enough Ca2+ in order to close gate
which ion channels have -
- p-loop
- the most a helices across the membrane
- S1 and S4
- plugging mechanism
- gated
- all, this is the pore
- voltage gated can have from 6-24 (simple channel has 2, TRP and ligand-gated have 6)
- voltage gated channel as these are the voltage sensing domains
- voltage-gated and TRP
- all (tho simple channels don’t have to be gated)
similarities and difference between the P2X family, glutamate family and nicotinic receptor family?
all Na+ and K+ selective (some can be Ca2+ selective)
each have different subunits within the families that can combine in many different ways
differences -
P2X = trimeric, ATP is the ligand
glutamate = tetrameric
nicotinic = pentameric (includes nAChRs, 5-HT, GABA)
disease caused by a mutation in nAChRs in the hippocampus?
autosomal dominant frontal lobe epilepsy
mutation causes slow unblocking of the channels which somehow causes an inc in NT release = seizures
what are some key features of nAChRs?
pentameric/cys-loop
4TM domains with intracellular and extracellular loop between M3 and M4
more ‘pliable’ - allow Na and K and Ca through
example of how subunits creating diversity in receptors is ideal for drug targets?
nAChRs are all over the brain and at NM junctions. treating for example tobacco dependency comes with the problem of not wanting to effect allllll the nAChRs and cause loads of side effects.
if the nAChRs involved in tobacco dependency have certain subunits this can hopefully be targeted
we know polymorphisms have been linked to tobacco dependency as well as resistance
glutamate receptors - how do these work?
main NT of the brain, has an inverted pore
ligand (glutamate) binds in clefts on the receptor that close as this happens like a clam, this closing is what pulls the pore open
glutamate receptors - how do they show diversity?
Three kinds, each with their own isoforms (AMPA with 4, NMDA and kainate each with 5 isoforms)
This diversity is generated by having more than one gene for glutamate receptors but also splicing/RNA editing
RNA splicing -
Each subunit for AMPA receptors has two isoforms, flip and flop. This is a result of alternate splicing of two exons
Flop = faster desensitisation rate and reduced current responses to glutamate than flip
how can RNA editing go wrong in glutamate receptors?
The M2 subunit - lines the pore so essential for selectivity - has an isoform called GluA2. This has a Q/R site - meaning a glutamine needs to be changed to an arginine. Without this editing pore is constantly open to Ca2+ = overexcited = seizures = early death in mice
