ligand-gated channels Flashcards by Emily Moore

functions of all ion channels:

transport ions across membrane

regulate membrane potentials

Ca2+ influx into cytoplasm

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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’

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subgroups of ion channels

Gating mechanism – voltage or ligand
ion selectivity of pore

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what are alpha helices

a right hand-helix conformation

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what are beta sheets

Beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a sheet.

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what are subunits

single protein that forms with others to form protein complex

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what are transmembrane domains

protein that spans the width of the membrane from the extracellular to intracellular sides usually a helical shape

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what are pores/p-loops

pocket where ion will bind

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how many human genes code for membrane channels

400

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primordal channel structure

two transmembrane domains
3 subunits
each subunit has two domains which surround the pore
basic structure of all ion channels

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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

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sodium/ calcium channels structure

6 domains duplicated
24 domains
4 subunits that make up domains

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ligand gated channel

6 transmembrane domains that surround a p loop

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K channel gates are controlled by

membrane potential
mechanical stress
ligand binding to C terminal

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functions of V gated ion channels

Na/K action in excitable cells
Ca2+ transport into cytoplasm for 2nd messengers to elicit response

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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

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what are transient receptor potential channels (TRP)

have common structural features with V-gated channels but evolved to sense chemicals and physical stimuli

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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

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no subunits in simple, V gated, TRP and ligand gated channels

2
4
4
4

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no TM helices in simple, V gated, TRP and ligand gated channels

2
6-24
6
6

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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 receptors function

mediate fast excitatory synaptic transmission in the central nervous system

NMDA = N-methyl-D-aspartate receptor 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 plasticity and mediating learning and memory functions - 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