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Molecular cellular biology > Ligand-gated ion channels > Flashcards

Ligand-gated ion channels Flashcards

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1
Q

what does selective expression of receptors and ligands allow?

A

In multicellular organisms, selective expression of certain receptors and the molecules involved in signal transduction allow cells to respond specifically to particular stimuli

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2
Q

what are ion channels?

A
  • A channel is a transmembrane protein that transports molecules from one side of the membrane to the other
  • They are specific e.g. Na+, K+ or Cl-
  • They can be open (non-gated) or use carries (gated)
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3
Q

what are the 3 essential functions of ion channels?

A
  1. transport ions across the membrane: secretion/absorption of fluids
  2. regulate membrane potentials e.g. in nerve and muscle cells
  3. calcium influx into cytoplasm: secretion and muscle contraction
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4
Q

what are the main structural features of all ion channels?

A
  • transmembrane proteins made up of 2 or more alpha-helices crossing lipid bilayer (transmembrane domains)
  • 2-6 subunits surround the pore
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5
Q

what are the exceptions to the main features of ion channels?

A

exceptions are Cl-, water and ammonia ion channels which each have a pore existing in the middle of a single subunit

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6
Q

how are ion channels classified?

A
  1. their gating mechanism: voltage or ligand
  2. the ion selectivity of the pore - defined by physical size of the pore and the amino acids that line the pore
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7
Q

what is an alpha-helix?

A
  • secondary protein structure
  • has a right-hand helix conformation
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8
Q

what is a beta-sheet?

A
  • secondary structure
  • beta strands are connected laterally by at least 2 or 3 backbone hydrogen bonds
  • forms a sheet
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9
Q

what are subunits?

A
  • single proteins which join with others to make a protein complex
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10
Q

what is a transmembrane domain (TM)?

A
  • protein that spans the width of the membrane from extracellular to intracellular sides
  • usually helical in shape
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11
Q

what is a p-loop/pore?

A

the pocket in which the ion will bind

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12
Q

how have ion channels evolved?

A
  • 400 genes in humans code for membrane channels

knowledge of structure reveals evolutionary relationships:
- The pH-regulated K+ channel KcsA from Streptomyces lividans serves as a model for all channels

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13
Q

what is the structure of a simple ion channel e.g. K+ channel?

A
  • TM helicase structures form a p-loop pore which is highly selective
  • 4 subunits, 2 TMs
  • on cytoplasmic side, TMs are tightly packed to form a gate
  • controlled by membrane potential, mechanical stress and ligands
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14
Q

what are the two main functions of voltage-gated ion channels?

A
  1. Na+ and K+ create APs in excitable cells
  2. Ca2+ is transported into cytoplasm where second messengers elicit cellular responses
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15
Q

what is the structure of voltage-gated ion channels?

A

based on similar structure to simple ion channel except:
- additional helices S1 and S4 form a voltage-sensing domain lateral to the subunits
- large polypeptides extend into cytoplasm
- plugging mechanism by voltage-sensing domains - allows channel to be gated by voltage
- 4 subunits
- 6-24 TMs
- contains p-loop, cytoplasmic anchors and plugging mechanism

example: voltage-gated potassium channel

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16
Q

what are Transient Receptor Potential (TRP) channels?

A
  • share common structural features with voltage-gated ion channels
  • evolved to sense chemicals and physical stimuli
  • 4 subunits
  • 6 TMs
  • responds to hot/spicy taste
  • contains P-loop, cytoplasmic anchors and plugging mechanism
  • no voltage-sensing domain
17
Q

what is the structure of ligand-gated ion channels?

A

similar structure to voltage-gated but controlled by ligand-binding:
- Transmembrane domains, binding domain faces out of the cell, proteins come together to form heteromeric/homomeric receptor
- Transmembrane domains form aqueous pore for ions to flow through
- When ligand binds, aqueous pore opens so that ions can move across gradient
o- Flow of ions generate a current which leads to changes in membrane potential
- 4 subunits, 6 TMs
- Channel gating is controlled by ligand binding
- has no plugging mechanism and no voltage-sensing domain

18
Q

give an example of a ligand-gated ion channel and describe its structure:

A

cyclic nucleotide-gated ion channel: senses cAMP or cGMP
- tetramer: 4 subunits
- 6 TMs
- S5 and S6 alpha-helical domains line central pore with p-loop controlling filter
- addition of regulatory domains to intracellular N and C terminals
- cyclic nucleotide-binding domain on C terminal opens a pore permeable to Na+ and Ca2+
- ligand must bind to 3 of the 4 sites for the channel to open, lose 1 and channel closes to give sharp conc-response curve
- calmodulin is bound to N-terminal. if calcium binds to N-temrinal, calmodulin provides negative feedback

19
Q

what are extracellular ligand-gated ion channels known as?

A

form distinct family of ionotropic receptors:
- Cys-loop type
- ionotropic glutamate type
- P2X type
- calcium-release type

20
Q

what is the general function of ionotropic receptors?

A
  • TMs regulate specificity of channels: if positively charged, they let anions through (Cl-), if negatively charged they let cations through (Na+, K+, Ca2+)
    -Na+/K+ selective channels control membrane excitability
  • channels with added permeability to calcium indirectly regulate activity of calcium-sensitive proteins
  • chloride-selective channels control membrane excitability by hyperpolarisation to reduce AP firing
21
Q

what is the structure of the Cys-loop type ionotropic receptor? give an example of this receptor type:

A
  • pentameric assembly: 5 subunits, 4 TMs

example: nicotinic acetylcholine receptor (nAChR)
- 5 subunits: alpha, beta, gamma and epsilon (1 can repeat)
- subunit composition can change -> selectivity of ions that can flow through
- each subunit has 4 TMs (M1, M2, M3, M4)with a large externally-facing N domain
- intracellular loop between M3 and M4
- M2 lines the pore and determines ion specificity

22
Q

what do the variety of subunits within ionotropic receptors achieve?

A
  • Different subunit combinations make up receptors in different parts of the brain
  • Complexity provides diversity and opportunity for drug targeting

E.g. nAChR-alpha4 subunit is involved in reward pathways and nicotine addiction

23
Q

how can targeting nAChRs help to treat nicotine addiction?

A

neuronal nAChRs exist as alpha2-10 and beta2-4, and each has different affinity depending on subunit composition and location:
- alpha4-beta2 are expressed in cortex and hippocampus and have high affinity to agonists nicotine and varenicline
- chronic exposure to nicotine leads to nAChR upregulation
- we can target these alpha4-beta2 receptors specifically, without affecting the other nAChRs that have different subunit compositions
- genetic studies show polymorphisms in CHRNA4 (alpha-4) and CHRNA6 (alpha-6) are linked to tobacco dependence but better cessation outcomes - can personalise treatment options
- rare variants are protective against nicotine dependency

24
Q

what mutation causes ADNFLE (autosomal dominant nocturnal frontal lobe epilespy)?

A

mutation in the M2 region of the human alpha-4 subunit (CHRNA4) of nAChR causes ADNFLE
- 9 mutations have been identified
- receptors have a delayed response to ACh - lag caused by the slow unblocking and recycling of receptors
- the ACh concentration dependence of use-dependent potentiation and delay in rising face is caused by slow unblocking of closed receptors
- this means there is an enhanced nAChR activity, so increased nicotinic-mediated transmitter release, leading to ADNFLE seizures

25
Q

what is the structure of ionotropic glutamate receptors?

A
  • tetrameric assembly: 4 subunits, 3 TMs
  • pore is inverted
  • activated by glutamate
  • forms as a dimer of dimers: the ligand-binding site is in a cleft that closes when occupied
26
Q

why are ionotropic glutamate receptors important?

A

vital to every aspect of brain function
- dysfunction of these receptors contributes to human disease

27
Q

how are ionotropic glutamate receptors diverse? what subcategories do they have?

A

Multiple genes, alternative splicing and RNA editing contribute to diversity (pharmacology, permeability and function) of glutamate receptors:

  1. AMPA = mediate fast excitatory synaptic transmission in CNS
  2. NMDA (N-methyl-aspartate receptor) = involved in learning and memory (slower than other isoforms)
  3. Kainate = similar to AMPA but lesser role at synapses -> linked to schizophrenia, depression and Huntington’s
28
Q

how does RNA splicing have consequences in AMPA receptor subunits?

A
  • Each subunit exists as two splicing isoforms - flip & flop
  • Alternative splicing of two exons in the primary transcript = two protein isoforms with different domain in the extracellular loop
  • Causes them to have different kinetic properties: Flop = faster desensitization rate and reduced current responses to glutamate than flip
29
Q

how does RNA editing have consequences in AMPA receptor subunits?

A
  • 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
  • Effect of GluA2 Q/R editing on channel Ca2+ permeability – stops Ca2+ entering the cell
  • Mutant mice lacking enzyme responsible for RNA editing prone to seizures and early death
30
Q

what is an example of dysfunction in NMDA receptors?

A
  • The NMDA receptor is thought to be important for controlling synaptic plasticity and mediating learning and memory functions
  • Excess stimulation of NMDA in stroke leads to neuron death
31
Q

how can dysfunction of RNA modification lead to pathogenic conditions in ionotropic glutamate receptors?

A

Downregulation of GluA2 Q/R editing in the motor neurons of ALS patients = increase in Ca2+ permeable AMPA receptors causes damage due to glutamate excitotoxicity
- Downregulation of the editing enzyme ADAR2 not a mutation in the editing site

In glioblastoma, decreased ADAR2 activity correlated with increased malignancy
- Increase in Ca2+ = Akt pathway promoting proliferation and tumorigenesis
- This was reversed when GluA2 Q/R was edited

Potential targets for therapeutic applications

32
Q

what is the structure of P2X ionotropic receptors?

A
  • trimeric assembly: 3 subunits, 2 TMs
  • ATP-gated ion channel
  • large extracellular domain
  • 3 ATP molecules are needed to open the channel
  • Widely expressed
  • P2X1-7 subtypes of subunits
33
Q

why are ionotropic receptors good drug targets?

A

they have diverse and specific subunits so drugs can be made to specifically target those subunits, meaning other ionotropic receptors without those subunits will be unaffected

34
Q

give an example of how dysfunction in receptor expression leads to physiological conditions:

A

in macrophages, activation of caspase 1 inflammasome results in release of cytokines for inflammation
- These receptors for caspase 1 can be targeted to treat inflammation

Molecular cellular biology (13 decks)

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