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aa PA30251 > Ligand-gated ion channels 1 > Flashcards

Ligand-gated ion channels 1 Flashcards

1
Q

What are ligand-gated ion channels

A
  1. multiple subunit proteins which form cation or anion channels
  2. Incorporate a receptor and open only when the receptor is occupied by an agonist
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2
Q

What are channel properties determined by

A
  1. The subunit composition
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3
Q

What channel properties are changed

A
  1. agonist activation
  2. ion permeation
  3. conductance properties
  4. deactivation / desensitisation kinetics
  5. receptor localization
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4
Q

What are examples of different sizes of ligand gated ion channels

A
  1. Puinergic- 3 subunits
  2. Glutameric- 4 subunits
  3. GABA- pentameric
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5
Q

What are the different subunits of GABA

A
  1. Alpha
  2. Beta
  3. Gamma
  4. Delta
  5. Epsolon
  6. Rho
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6
Q

What are the different types of GABA receptors

A
  1. GABAA - Cl- ion channel
  2. GABAB - GPCR
  3. GABAC - Cl- ion channel
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7
Q

Describe structure of GABAARs

A
  1. Heteropentameric ion channels
  2. 2 alpha subunits, 2 beta subunits and gamma subunit
  3. Biding site for GABA at interfaces of alpha and beta subunits
  4. Aqueous pore in centre
  5. 4 transmembrane spanning domains
  6. Cis loop on extracellular surface on N-terminal domain
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8
Q

What is the most common subunit combination for GABAAR

A
  1. 2X Alpha 1
  2. 2x beta 2
  3. 1x gamma 2
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9
Q

What does different combinations of GABAA subunits mean

A
  1. One transmitter can do lots of different jobs that is determined by the function of the GABAA receptor- governed by subunits
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10
Q

What do all alpha subunits have

A
  1. Characteristic cys-cys pair in the N-terminal extracellular domain, essential for agonist binding
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11
Q

Where is there homology between the receptor subunits

A
  1. Transmembrane domain M1, M2, M3, M4
  2. Ligand binding region are variable
  3. Intracellular loop interacts with proteins inside of cell- variable
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12
Q

Describe agonist activation o

A
  1. Binding of GABA to N-terminal domain at interface of a/b subunits
  2. Opening of ion-selective pore- anion
  3. Transmembrane 2 domains- Conserved leucine residue is implicated in the gating of the ion channel
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13
Q

Describe channel opening of ACh (analogous to GABAA)

A
  1. Agonist binding induces change to cause channel to open
  2. Closed state - two alpha subunits and transmembrane 2 domain facing into pore
  3. Weak interactions between inner helices causes hydrophobic constriction of ion channel
  4. In presence of ACh, the ion channel opens
  5. Binding induces rotation in extracellular beta sheets- conformational change which opens channel
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14
Q

Describe a model for agonist activation of LGIC with two agonist binding sites

A
  1. Agonist binding increases the probability of ion channel opening
  2. Measurement of functional binding-gating can only be done using single-channel analysis
  3. K = binding constant
  4. *= channel opening
  5. Efficacy = Beta/alpha
  6. Beta= opening rate constant
  7. Alpha= shutting rate constant
  8. If both binding sites are occupied get bigger opening
  9. Model of alpha and beta- if ligand only binds to one part it doesn’t open fully- otherwise just partial opening
  10. Need both to be ligated to open fully
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15
Q

Describe example of how subunit combination of GABAA can change pharmacology

A
  1. Functional GABAA receptor is a pentamer of at least a/b or a/b/g
  2. Agonist affinity and efficacy at the GABA binding site is altered by a subunit
  3. THIP and P4S are partial agonists at the GABAAR have the highest affinity and efficacy on a6b1g2 and the lowest affinity and efficacy on a4b1g2
  4. Depending on the composition of channel agonists can bind and open channel different amounts
  5. Compared effects of agonist on electrophysiological recordings
  6. GABA only – Alpha 4- low efficacy
  7. But alpha 6 much higher efficacy
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16
Q

What is ion selectivity based on

A
  1. usually refers to relative permeability
  2. pore size
  3. presence of charged groups lining the pore
17
Q

Describe what effect GABAA when agonist bound

A
  1. GABAA agonist induces conformational change which increases permeability of central pore to Cl-
  2. Generally leads to hyperpolarization and inhibition of network activity
18
Q

What determines the specificity to ions

A
  1. Permeable to specific ions – size of pore and charge of groups determines which ions
  2. Depends on amino acids - Basic, polar, acidic etc
19
Q

What is an inhibitory synapse and give example

A
  1. e.g. g-aminobutyric acid
  2. Generates inhibitory postsynaptic potential (IPSP)
  3. When ion channel opens cl- diffuse into cell taking negative charge into cell- hyperpolarises the membrane away from resting membrane making it more difficult to cause action potential
20
Q

What is the Nernst Equation measuring

A
  1. Ion flow through a channel
  2. The equilibrium potential for any ion (Eion) can be calculated using the Nernst equation
21
Q

What is the Nernst Equation

A
  1. Eion = 2.303 RT/zF log [ion] outside/[ion] inside
  2. Constants
  3. R = gas constant
  4. T = absolute temperature
  5. F = Faraday’s constant
  6. z = charge of the ion
  7. So really based on ions outside to inside – everything else are constants
22
Q

What type of ions do nAChR/5HT3 channels allow

A
  1. nAChR/5HT3 are cation channels
23
Q

What are the two models of ligand binding and channel opening

A
  1. Induced fit model
  2. Allosteric model
24
Q

What is the induced fit model of ligand binding

A
  1. binding of agonist to the receptor induces a conformational change in the region of ligand-binding site which propagates to the pore region and causes opening of the ion-conducting pore
25
Q

What is the the allosteric model of ligand binding

A
  1. receptor constantly undergoing spontaneous transitions between different conformations.
  2. Different conformations confer different affinity for ligand.
  3. Binding of an agonist typically stabilizes the channel in the open state.
26
Q

What are the determinants of IPSC kinetics

A
  1. Lifetime of GABA at the synapse- diffusion/reuptake mechanisms
  2. Postsynaptic GABAA receptor composition- IPSC decay rates vary from 10-100s of ms
  3. Single channel recording of receptors- some open for short some for longer- just based on different of one subunit
27
Q

Do ligand-gated ion channels show desensitisation

A
  1. Also exhibit desensitisation
  2. Mechanism not as clearly worked out as for gpcrs
  3. Same gabaa receptor just different GABA application times – longer time= desensitisation
28
Q

What is desensitisation of GABAARs altered by

A
  1. Desensitization of GABAARs is altered by subunit composition
  2. Desensitization is altered by endogenous factors (Zn, phosphorylation) and by pharmacological agents (e.g. BZ)
  3. Effects of subunit composition not well established – big difference between delta and gamma-2 containing proteins
29
Q

Describe GABAA receptor localization

A
  1. in situ hybridization study for subunit mRNA in brains
  2. some individual alpha subunits have discrete distribution
  3. others have overlapping distribution
  4. g subunit important for trafficking Rs to cell surface
30
Q

Where can GABAAR be found

A
  1. In synpase
  2. Extra synaptically
31
Q

Describe activity of synaptic GABAAR

A
  1. Phasic activation – when nerve fires
  2. Transient inhibition
  3. Hi [GABA]
  4. a1,2,3 (5), g2 containing Rs
  5. BZ-sensitive
  6. Anxiolytic
  7. anticonvulsant
32
Q

Describe activity of extrasynaptic GABAA receptors

A
  1. Persistent activation
  2. Tonic inhibition at low levels
  3. Low [GABA] but are active more or less all the time
  4. a4,6 (5), delta containing Rs
  5. BZ in-sensitive (not a5)
  6. Alcohol
  7. Anaesthetics
  8. Neurosteroids

aa PA30251 (9 decks)

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