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+ BIOL 371 > Lecture 11: Ionotropic Neurotransmitter Receptors > Flashcards

Lecture 11: Ionotropic Neurotransmitter Receptors Flashcards

1
Q

What are neurotransmitter receptors?

A

transmembrane proteins found in postsynaptic neuron of a chemical synapse

activated by binding of neurotransmitter

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2
Q

What does the activation of a neurotransmitter receptor trigger effects on?

A

triggers effects on membrane potential of postsynaptic cell, its intracellular signalling pathways, or both

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3
Q

What type of effects can be triggered by activation of a neurotransmitter receptor? What are the types defined by?

A

excitatory or inhibitory – classification is defined by whether it makes the AP more or less likely to fire an AP

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4
Q

Can the same neurotransmitter have different effects on different synapses?

A

yes

there are more types of receptors than types of neurotransmitters

different types of receptors can generate distinct effects, even when they are activated by the same neurotransmitter

the same neurotransmitter can have rapid, short-lasting effects OR slow, prolonged effects on the membrane potential (in either direction), depending on which kind of receptor protein it has bound to

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5
Q

Can the same neurotransmitter have different effects?

A

yes – by activating different receptors

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6
Q

What is polarity?

A

direction of current or PSP

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7
Q

What is latency?

A

time to response onset

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8
Q

What is duration?

A

time from response onset to end

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9
Q

What should the excitatory and inhibitory terminology describe?

A

RECEPTOR (not neurotransmitter)

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10
Q

What is the Receptor Doctrine?

A

effects of a neurotransmitter-receptor pair on the state of the postsynaptic cell are determined by properties of the receptor, NOT the transmitter molecule (which is just the key that turns the receptor on)

(neurotransmitters are NOT described as excitatory or inhibitory)

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11
Q

What are the two classes of neurotransmitter receptors?

A
  • ionotropic receptors

- metabotropic receptors

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12
Q

What is an ionotropic receptor?

A

(ligand-gated) ion channel that directly affects membrane potential when the neurotransmitter binds and unbinds

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13
Q

What is a metabotropic receptor?

A

transmembrane protein that triggers intracellular biochemical cascades when the neurotransmitter binds

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14
Q

How do metabotropic receptors cause a change in Vm?

A

intracellular biochemical cascades are triggered when the neurotransmitter binds, which often leads (after a delay) to opening or closing of separate ion channels – Vm is (usually) affected, but indirectly

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15
Q

What are the 5 properties used to classify ionotropic receptors?

A
  • selectivity
  • gating
  • conductance
  • kinetics
  • regulation
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16
Q

What is selectivity?

A

which different ions can pass through the channel

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17
Q

What is gating?

A

what factors determine whether the channel is open or closed

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18
Q

By definition, what type of gating do ionotropic receptors have?

A

ligand-gated

but can also be sub-classified by:

  • binding affinity
  • extra gating requirements (ie. voltage)
  • co-transmitter requirements
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19
Q

What is conductance?

A

how many ions can pass through the channel per unit time

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20
Q

What is kinetics?

A

how fast the channel gates open and close, and whether the channel inactivates itself after it has opened

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21
Q

What is regulation?

A

what non-endogenous ligands the channel is sensitive to

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22
Q

What is the structure of ionotropic receptors?

A

quaternary structure – are assembled from multiple (usually non-identical) protein subunits (coded for by different genes)

sometimes subunit types even come in multiple different isoforms, also coded for by distinct but closely related genes (ie. α1-10, β1-4)

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23
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

What are nicotinic AChRs responsible for?

A

responsible for EPCs in NMJs

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24
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

What does the basic structure tell us?

A

demonstrates key features that are found in all ionotropic receptors (ligand-gated ion channels)

  • binding sites: (extracellular) for the ligand
  • linker structures: couple binding to opening and closing of the pore
  • centra pore: permeable to ions
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25
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

Selectivity – Describe a method used to figure out which ions can pass through a channel.

A
  1. find reversal potential (Erev)
  2. compare Erev to known Eion values
  3. test ion permeability by manipulating Eion (permeable ions shift Erev)
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26
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

Selectivity – What is the Erev of nAChRs?

A

0mV – and is sensitive to cation concentrations

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27
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

Selectivity – Is nAChR a selective or non-selective cation channel? Why?

A

non-selective cation channel – monovalent cations of various sizes are equally permeable

this is because the channel’s selectivity filter (narrowest part of pore) is relatively large

28
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

What effects (excitatory/inhibitory) do non-selective cation channels/receptors always have?

A

excitatory effects – producing EPSCs/EPSPs

because neurons (and muscle cells) spend most of their time at or near RMP, and very little time at or above 0 mV, Na+ influx is usually most of the current carried by a non-selective cation channel when it is activated

29
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

Would you expect the selectivity filter in the nAChR pore to be lined with negative or positive charges?

A

negative charge

30
Q

TRADE OFF: nAChRs are non-selective because they have much wider pores than VG-K channels. Their net effect is still excitatory, but wouldn’t they be even more excitatory if they tightened their filters, and excluded K+? That would make their ERev a positive value, increasing their net driving force when they open, and thus increasing their inward currents.

Why would nAChRs trade a reduction in net inward current at negative Vm for a larger pore?

A

larger pore could increase the channel’s conductance, increasing the amount of current it passes per unit time

  • although keeping some selectivity for K+ tends to decrease driving force (which decreases current travelling through pore), a larger boost in conductance (by widening the selectivity filter and allowing more ions to come through) than loss in driving force will increase the overall current flowing through the receptor, which will increase the rate cell is depolarized
  • VgK channel has 10x less conductance (number of ions going through) than nAChR
31
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

What is the structure of the receptor?

A

complexes of five subunits – functional nAChR requires at least two α subunits, and three other subunits of various types

different cells express different combinations of subunits

32
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

What does the α subunits of the receptor contain?

A

ACh binding site – each nAChR binds two molecules of ACh in order to open (has two α subunits)

33
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

What are the receptor subunit types?

A

α, β, γ, δ, and ε

34
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

Selectivity – Why are there different subunit classes in these receptors?

A

gives the channel distinct properties

  • usually relatively subtle differences in kinetics
  • sometimes consequential effects on selectivity
35
Q

Case Study 1: Nicotinic Acetylcholine Receptor (nAChR)

Regulation – What affects how channel subtypes respond to toxins and drugs

A

subunit composition – different subunits often have different sensitivity to non-endogenous ligands that bind to, and alter the function of the receptors (drugs and toxins)

these drugs can be either agonists or antagonist

36
Q

What is an agonist?

A

non-endogenous molecule that can activate an ion channel or cellular receptor (mimics the action of the natural ligand)

whether a molecule is an agonist does NOT depend on effect on the cell – only effect on the receptor

37
Q

What is an antagonist?

A

non-endogenous molecule that can block or prevent activation of an ion channel or cellular receptor (blocks the action of the natural ligand)

whether a molecule is an antagonist does NOT depend on effect on the cell – only effect on the receptor

38
Q

Case Study 2: GABAA Receptor

What is gamma-amino-butyric acid (GABA)?

A

the endogenous ligand for most inhibitory receptors in nervous system

known to be an amino-acid derivative which had been chemically purified from both mammalian brain extracts and ECF after strong stimulation of known inhibitory synapses

39
Q

Case Study 2: GABAA Receptor

What can GABA do to inhibitory neuron stimulation?

A

can substitute for inhibitory neuron (I) stimulation, and occludes the effects of inhibitory stimulation

40
Q

Case Study 2: GABAA Receptor

What are GABA A receptors?

A

ionotropic inhibitory receptors with permeability to anions

41
Q

Case Study 2: GABAA Receptor

What system uses GABA as their neurotransmitter?

A

like peripheral inhibitory synapses in the crustacean (such as those studied by Kuffler), most of the inhibitory synapses in the vertebrate CNS (in particular in the brain, rather than the spinal cord) use GABA as their neurotransmitter

42
Q

Case Study 2: GABAA Receptor

What is the structure of the receptor?

A

multimeric protein composed of five subunits (like nAChRs)

subunits have positively charged amino acids that form a ring within the pore which is the selectivity filter (unlike nAChRs, which have negative charges)

43
Q

Case Study 2: GABAA Receptor

How many GABA molecules must the receptor bind to open?

A

2

44
Q

Case Study 2: GABAA Receptor

Are the receptors selective or non-selective?

A

selective

positively charged amino acids confer anionic selectivity – only negatively charged ions, especially chloride, can pass through the pore when it is open (Erev ≈ ECl)

45
Q

Case Study 2: GABAA Receptor

What is the Erev of GABAARs?

A

ECl

46
Q

Case Study 2: GABAA Receptor

How can the same subunits of GABAA receptors show different responses? Is this a change in subunit expression?

A

NOT a change in expression – has nothing to do with the type of receptor expressed in embryonic post-synaptic cells

it is caused by changes in the ion transporters that maintain chloride gradients – the same subunits can show different responses if ion concentration gradients change

47
Q

Case Study 2: GABAA Receptor

Compare immature neurons to mature neurons in terms of Cl-.

A

IMMATURE NEURONS: express a transporter (NKCC) that causes high intracellular [Cl-], making ECl less negative
- when a chloride channel like GABAA opens, outward flow of anions causes a depolarization that can cross VTh

MATURE NEURONS: express a transporter (KCC2) that causes low intracellular [Cl-], making ECl more negative
0 when a chloride channel like GABAA opens near VTh, there will be net inward flow of anions, causing a hyperpolarization

48
Q

Case Study 2: GABAA Receptor

GABAA receptor subunits are targets for many what?

A

psychoactive drugs, especially downers – many well-known sedatives or depressants have known binding sites within GABAA receptors

49
Q

Case Study 2: GABAA Receptor

What are the different pharmacological profiles of psychoactive drugs in part due to?

A

due to their affinity (ability to bind) for different GABA subunit isoforms

ie. GABAA receptors that lack γ subunit are insensitive to benzodiazepines, but sensitive to alcohol

50
Q

Case Study 2: GABAA Receptor

Many well-known sedatives or depressants have known binding sites within GABAA receptors. Would you predict these drugs are acting as agonists or antagonists of GABAARs?

A

agonists – they increase effect of GABA by mimicking GABA (which means GABA is not actually needed to turn these receptors on)

51
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What is glutamate?

A

most common neurotransmitter (for many synapses) in vertebrate CNS

52
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What is glutamate mediated by? How do we know?

A

mediated by excitatory, ionotropic receptors (iGluRs)

because synapses typically have rapid excitatory effects on the postsynaptic neuron

53
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What are excitatory, ionotropic receptors (iGluRs)?

A

non-selective cation channels – like nAChRs

54
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What is the Erev for excitatory, ionotropic receptors (iGluRs)?

A

-10 to 0 mV

55
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What are the two major types of glutamate receptors in our brain? What is the third type?

A 
AMPA receptors (GluARs) 
NMDA receptors (GluNRs)

kainate receptors

56
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

There are 2 different patterns of responses associated with different agonist/antagonist pairs. Why?

A

due to presence of two distinct classes of iGluRs

  • AMPA receptors (GluARs)
  • NMDA receptors (GluNRs)
57
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What are AMPA receptors (GluARs) activated by? Antagonized by?

A

activated by glutamate or AMPA
- AMPA induces rapid, transient, high amplitude currents

antagonized by CNQX
- CNQX blocks the rapid, transient component

58
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What are NMDA receptors (GluNRs) activated by? Antagonized by?

A

activated by glutamate or NMDA
- NMDA induces currents that are slower onset, and lower amplitude, but more persistent

antagonized by APV (and many other drugs)
- APV blocks the slow persistent component of the total current (control)

59
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What are some properties of both AMPA receptors (GluARs) and NMDA receptors (GluNRs)?

A
  • both are cation-permeable receptors

- both are named after their respective selective agonists

60
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What are kainate receptors?

A

(third type of iGluRs) receptors that are related to AMPARs, but have key differences in a number of properties, and are less common in the brain

61
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

What is the structure of all iGluRs?

A
  • iGluR types use four subunits around their central pore (not five) and open by different types of conformational changes
  • all receptor types have a different quaternary structure than nAChRs or GABAARs
62
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

Do most vertebrate glutamatergic synapses use NMDARs or AMPARs?

A

most use use both NMDARs and AMPARs together – both glutamate receptor channel types are present in most vertebrate synapses within the brain (as seen in both physiological/pharmacological and anatomical staining studies)

63
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

GluARs vs. GluNRs – Selectivity

A

NMDARs are permeable to Ca2+, K+, and Na+

but most AMPARs are not

64
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

GluARs vs. GluNRs – Gating

A

NMDARs require glycine and glutamate to open, and they are also voltage-gated in the presence of physiological levels of Mg2+

because of their voltage-gating, NMDARs will not always participate in depolarizing the postsynaptic cell from RMP, but they are targets for many drugs (both therapeutic and recreational)

65
Q

Case Study 3: Distinct Ionotropic Glutamate Receptor Classes

GluARs vs. GluNRs – Kinetics

A

NMDARs open more slowly, but for longer durations than AMPARs

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