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adv mol cell > ligand-gated channels > Flashcards

ligand-gated channels Flashcards

1
Q

functions of all ion channels:

A

transport ions across membrane

regulate membrane potentials

Ca2+ influx into cytoplasm

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2
Q

structural features of ion channels

A
  • 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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3
Q

subgroups of ion channels

A
  • Gating mechanism – voltage or ligand
  • ion selectivity of pore
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4
Q

what are alpha helices

A

a right hand-helix conformation

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5
Q

what are beta sheets

A

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

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6
Q

what are subunits

A

single protein that forms with others to form protein complex

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7
Q

what are transmembrane domains

A

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

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8
Q

what are pores/p-loops

A

pocket where ion will bind

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9
Q

how many human genes code for membrane channels

A

400

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10
Q

primordal channel structure

A
  • two transmembrane domains
  • 3 subunits
  • each subunit has two domains which surround the pore
  • basic structure of all ion channels
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11
Q

potassium channel structure

A
  • 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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12
Q

sodium/ calcium channels structure

A
  • 6 domains duplicated
  • 24 domains
  • 4 subunits that make up domains
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13
Q

ligand gated channel

A

6 transmembrane domains that surround a p loop

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14
Q

K channel gates are controlled by

A
  • membrane potential
  • mechanical stress
  • ligand binding to C terminal
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15
Q

functions of V gated ion channels

A
  • Na/K action in excitable cells
  • Ca2+ transport into cytoplasm for 2nd messengers to elicit response
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16
Q

structural differences between V gated ion channels and simple ion channels:

A
  • 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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17
Q

what are transient receptor potential channels (TRP)

A

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

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18
Q

how do ligand-gated ion channels work

A
  • 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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19
Q

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

A

2
4
4
4

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20
Q

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

A

2
6-24
6
6

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21
Q

are simple, V gated, TRP and ligand gated channels gated?

A

no
yes (changes in memb pot)
yes
yes (chem transmitters)

22
Q

do simple, V gated, TRP and ligand gated channels have a p loop?

A

YES ALL

23
Q

do simple, V gated, TRP and ligand gated channels have cytoplasmic anchors?

A

no
yes
yes
yes

24
Q

do simple, V gated, TRP and ligand gated channels have voltage sensing domains?

A

no
yes - v gated
no
no

25
Q

do simple, V gated, TRP and ligand gated channels have a plugging mechanism?

A

no
yes - v gated
yes - TRP
no

26
Q

functional examples of simple, V gated, TRP and ligand gated channels?

A

simple = secretion/absorption of fluids
v gated = excitable cells
TRP = hot/spicy taste
ligand-gated = olfaction

27
Q

families of ionotropic receptors:

A

ATP P2X
glutamate
nicotinic

28
Q

do subunits in the brain vary with location?

A

Different subunit combinations make up receptors in different parts of the brain

29
Q

pentameric receptors structure

A
  • 4 domains
  • EC domain recognises transmitters
  • 5 subunits make up e.g nicotinic acetylcholine receptors
30
Q

tetrameric receptors structure

A
  • EC ligand binding site
  • 3 domains
31
Q

trimeric receptor structure

A
  • 2 domains
  • binding site for ATP in EC domain
  • TM regulates specificity of channels
32
Q

cys-loop type receptor - nicotinic acetylcholine receptor structure

A
  • in muscle
  • 5 subunits
  • 4 TMs (M1-4)
  • large external facing N domain and intracellular loop between M3 and M4
  • M2 lines pore
33
Q

targeting nicotinic receptors for nicotine addiction

A
  • 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
34
Q

mutation in nAChR and autosomal dominant nocturnal frontal lobe epilepsy

A
  • Mutations in the M2 region of the human α4 neuronal nicotinic subunit cause ADNFLE
  • Enhanced receptor function = increased nicotinic-mediated transmitter release = ADNFLE seizures
35
Q

glutamate receptors structure

A
  • 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
36
Q

AMPA receptorsfunction

A

mediate fast excitatory synaptic transmission in the central nervous system

37
Q

NMDA = N-methyl-D-aspartatereceptor function

A
  • involved in learning and memory
  • slower than other isoforms
38
Q

Kainate receptor function

A
  • similar to AMPA but lesser role at synapses
  • linked to Schizophrenia, depression and Huntingtons
39
Q

functional consequences of RNA processing in AMPA receptor subunits

A

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

40
Q

dysfunction of glutamate receptors

A
  • important for controlling synaptic plasticityand mediating learning and memoryfunctions
  • Excess stimulation of NMDA in stroke leads to neuron death
41
Q

dysfunction of RNA modifications → ALS

A

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

42
Q

dysfunction of RNA modifications → glioblastoma

A

decreased ADAR2 activity correlated with increased malignancy
Increase in Ca2+ = Akt pathway promoting proliferation and tumourigenesis

43
Q

P2X receptors structure

A
  • 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
44
Q

pathological conditions associated with P2X/trimeric

A

hearing loss
pain
inflammation
neurodegen disease

45
Q

pathological conditions associated with glutamate/tetrameric

A

excess NMDA in stroke -> death

46
Q

pathological conditions associated with cys-loop/pentameric

A

epilepsy

47
Q

The selectivity for specific ions is determined by

A

the structure of the filter and amino acids lining the pore

48
Q

function of an ion channel is largely determined by its

A

ion selectivity and gating mechanism

49
Q

Gating of ion channels is regulated by

A

voltage or ligand binding

50
Q

Diversity and specificity of receptors are useful because

A

they provide targets for drugs/inhibitors that can aid in the treatment of human conditions

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