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+ BIOL 371 > Lecture 12: Metabotropic Neurotransmitter Receptors > Flashcards

Lecture 12: Metabotropic Neurotransmitter Receptors Flashcards

1
Q

What can metabotropic receptor activation lead to?

A

can lead to delayed, sustained PSPs – leads the opening of a potassium-selective ion channel

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2
Q

What type of responses do metabotropic receptors produce?

A

slow, but sustained and diverse responses

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3
Q

What are some consequences that arise from employing intracellular cascades for signalling?

A
  • delay: latency of ~100ms - 1000ms between reception of the signal and effects on the cell
  • persistence: effects have sustained duration (from seconds to 10-15 minutes), and outlast the presence of neurotransmitter within the synaptic cleft
  • diverse responses: he same metabotropic receptor can simultaneously trigger a number of different effects in the same cell (ie. more than just a change in Vm)
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4
Q

Can metabotropic receptor responses differ even when they share neurotransmitters?

A

yes – same neurotransmitter can have opposite responses by acting on different subtypes of metabotropic receptor

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5
Q

What does the muscarinic M1 receptor do?

A

triggers depolarization of the cell when activated by ACh by inhibiting a K+ conductance

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6
Q

What does the muscarinic M2 receptor do?

A

triggers hyperpolarization of the cell when activated by ACh by enhancing a K+ conductance

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7
Q

What does the adrenergic 𝛼1A receptor do?

A

(norepinephrine receptor) triggers vasoconstriction by enhancing smooth muscle contraction

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8
Q

What does the adrenergic 𝛽2 receptor do?

A

(norepinephrine receptor) triggers vasodilation by reducing smooth muscle contraction)

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9
Q

What family of proteins do metabotropic receptors belong to?

A

all belong to GPCR superfamily of proteins

NOTE: all metabotropic receptors are GPCRs, but not all GPCRs are neurotransmitter receptors

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10
Q

What is another name for metabotropic neurotransmitter receptors?

A

g-protein coupled receptors (GPCRs) – reflects their association with g-proteins

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11
Q

What are g-proteins?

A

intracellular signalling proteins

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11
Q

What are g-proteins?

A

intracellular signalling proteins

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12
Q

What are some ligands that GPCRs detect?

A
  • endogenous ligands (these include neurotransmitters and hormones)
  • olfactory and gustatory ligands, and light
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13
Q

What are some structural features of all GPCRs?

A
  • 7 transmembrane (TM) domains, organized in a precise sequence
  • no ion-permeable transmembrane pore
  • intracellular G-protein binding site
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14
Q

What are some structural features of all metabotropic receptors?

A
  • all features of GPCRs (3)

- and extracellular ligand binding site

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15
Q

What are the two aspects of GPCR signalling you need to know for this course?

A
  • how activating a GPCR leads to activation of g-proteins – and how g-proteins are inactivated
  • how activated g-proteins lead to biochemical signalling cascades – and how this differs between different g-protein subtypes
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16
Q

What do g-proteins bind?

A

guanosine phosphates

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17
Q

What do g-proteins work closely with?

A

they are the intracellular partners of GPCRs – act as intracellular molecular switches, transducing signals detected by GPCRs into intracellular biochemical pathways

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18
Q

Where are g-proteins found?

A

in all eukaryotic cells

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19
Q

What are g-proteins named for?

A

their ability to bind the signalling molecule GTP, or its inactive relative GDP

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20
Q

How are g-proteins activated?

A
  • inactive g-protein contains a GDP molecule in its ‘guanosine’ binding site
  • activation of a GPCR (bound to neurotransmitter or agonist) catalyzes activation of the g-protein by promoting exchange of GDP for a new GTP molecule
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21
Q

What are the 2 types of g-proteins?

A

monomeric g-protein

heterotrimeric g-protein

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22
Q

Which type of g-protein is used in neurotransmitter synaptic signalling?

A

heterotrimeric G-proteins – most (if not all) GPCRs that respond to neurotransmitter bind to heterotrimeric G-proteins

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23
Q

Which type of g-protein is more common?

A

heterotrimeric G-proteins

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24
Q

What are monomeric g-proteins also known as?

A
  • small GTPases

- Ras superfamily

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25
Q

What are monomeric g-proteins important for?

A

cell growth responses

  • Ras and other monomeric G-proteins are important for cell growth and division
  • in neurons, they have roles in dendrite and axonal growth, synapse formation, and remodelling (but not neurotransmitter signalling)
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26
Q

What are monomeric G-proteins activated by?

A

GTP binding – BUT they do not directly associate with GPCRs

GPCRs activate monomeric G-proteins by using adaptor proteins and/or guanosine exchange factor proteins (GEFs)

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27
Q

What is the structure of heterotrimeric G-proteins?

A

consist of three (different) subunits – when the complex is inactive (GDP bound to α subunit), the three subunits assemble together on a GPCR

  • α subunit
  • β and γ subunit
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28
Q

What do α subunits of heterotrimeric G-proteins do?

A

bind GDP or GTP

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29
Q

What do α subunits of heterotrimeric G-proteins do when activated (GTP-bound)?

A

they diffuse away from GPCR and affect activity of other intracellular proteins

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30
Q

What do β and γ subunits of heterotrimeric G-proteins do?

A

functional unit – when α subunit binds a new GTP and becomes activated, β and γ separate from α and can also affect certain intracellular proteins

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31
Q

What do GTPase activating proteins (GAPs) do?

A

promote inactivation of G-proteins by catalyzing hydrolysis of GTP (back to GDP)

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32
Q

How many kinds of g-protein can each GPCR bind to?

A

can typically only bind to (and thus activate) one kind of G-protein

this means that more than one GPCR is often able to activate the same kind of G-protein

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33
Q

How many kinds of g-protein can each GPCR bind to?

A

can typically only bind to (and thus activate) one kind of G-protein

this means that more than one GPCR is often able to activate the same kind of G-protein

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34
Q

How do g-proteins mediate signal transduction cascades?

A

through the production of second messengers

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35
Q

What are the 3 key ideas to remember for g-protein-mediated signal transduction?

A
  • cascades
  • amplification
  • protein kinase
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36
Q

What are cascades?

A

multi-step pathways where one step catalyzes the production/activation of a distinct molecule/enzyme for the next step

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37
Q

What is amplification?

A

at each step of a cascade, one activated molecule can make many more of the units in the next step

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38
Q

What are protein kinases?

A

enzymes which catalyze the addition of phosphate groups onto other proteins

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39
Q

G-protein-mediated Signal Transduction

A

ligand (first messenger) + receptor → (amplification) → g-protein → enzyme → (amplification) → second messenger → protein kinase → (amplification) → phosphate transferred to target proteins

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40
Q

What are messengers?

A

ligands – molecules whose function is to bind specific receptors or enzymes within a signalling pathway, and switch that protein on or off

41
Q

What are regulators?

A

molecules that bind to enzymes and alter the ongoing activity of those enzyme

42
Q

What are effectors?

A

molecules that actually make a direct change to physiology of cell, rather than continuing the cascade

43
Q

The definition of messengers and regulators can, and does overlap a lot. When are you more likely to use the term ‘regulator’?

A

if the targeted enzyme is affecting effector proteins, not making a new type of messenger molecule

44
Q

What are the 3 types of messengers in cascades?

A
  • first messengers
  • second messengers
  • third messengers
45
Q

What are first messengers?

A

extracellular ligands that bind to surface receptors (neurotransmitters, hormones, neuropeptides)

46
Q

What are some functions of first messengers? (2)

A
  • fast PSPs

- produce second messengers

47
Q

What are second messengers?

A

intracellular molecules that regulate enzymes and channels (Ca2+, cyclic nucleotides, DAG, IP3)

this level can also include transducer proteins (ie. G-proteins, calmodulin), but they are not technically classified as second messengers because they are proteins (although they have some common features)

48
Q

What are some functions of second messengers? (5)

A
  • slow PSPs
  • modify ion channels
  • local structural changes
  • local metabolic changes
  • produce 3rd messengers
49
Q

What are third messengers?

A

molecules that enter the nucleus and interact with DNA (DNA-binding proteins/transcription (co-)factors)

50
Q

What are some functions of third messengers? (4)

A
  • gene expression
  • protein synthesis
  • global structural changes
  • global metabolic changes
51
Q

What is the difference between a regulator and a second messenger?

A
  • second messenger turns it on

- regulator can modify it

52
Q

How are Gα subunits classified?

A

into five groups based on the intracellular pathways (targets) they activate

53
Q

What are the 5 groups of Gα subunits?

A
  • G αs (stimulatory)
  • G αi/o (inhibitory)
  • G αq (‘queer’):
  • G αt (transducin)
  • G α12/13 (rho-mediated)
54
Q

What does the G αs (stimulatory) subunit group do?

A

activate adenylate cyclase (AC) and enhance cAMP signalling pathway

55
Q

What does the G αi/o (inhibitory) subunit group do?

A

inhibit adenylate cyclase (AC) and reduce cAMP signalling pathway

56
Q

What does the G αq (‘queer’) subunit group do?

A

activate phospholipase C (PLC) and enhance IP3/DAG signalling pathway, including ↑[Ca2+]

57
Q

What does the G αt (transducin) subunit group do?

A

activate cGMP phosphodiesterase (PDE) and reduce cGMP signalling pathway

58
Q

What does the G α12/13 (rho-mediated)) subunit group do?

A

interact with GEFs and members of Ras family of monomeric GTPases

59
Q

Remember: transduction cascades also activate mechanisms that can limit/turn themselves off.

A

-

60
Q

Cascade #1: ‘Stimulatory’ G αs Signalling Pathway

How does this pathway signal?

A

by increasing cAMP levels

61
Q

Cascade #1: ‘Stimulatory’ G αs Signalling Pathway

A
  1. Gαs-GTP binds to AC (primary enzyme)
  2. AC synthesizes cAMP (second messenger) from ATP
  • cAMP regulates cyclic nucleotide gated channels (effector proteins)
  • cAMP binds and activates PKA (cascade enzyme)
  • PKA phosphorylates many protein targets (effector proteins) – ie. Ca channels, K channels, GluARs, SNAREs, active zone proteins, other kinases and transcription factors
  • PKA targets phosphatases (PP), which remove phosphate groups so that effector proteins are not activated forever
  • PKA targets phosphodiesterases (PDE), which break down cAMP
62
Q

What is adenylyl/adenylate cyclase (AC)?

A

membrane-bound enzyme present in all cells that makes cAMP from ATP

63
Q

What are cyclic nucleotide gated channels?

A

intracellularly gated K+/cation channels

64
Q

Can transduction cascades turn themselves off?

A

yes – they activate mechanisms that can limit/turn themselves off

65
Q

Cascade #2: ‘Inhibitory’ G αi Signalling Pathway

How does this pathway signal?

A

by decreasing cAMP levels

65
Q

Cascade #2: ‘Inhibitory’ G αi Signalling Pathway

A
  1. Gαi-GTP binds to AC (primary enzyme)
  2. AC cannot synthesize cAMP (second messenger)

(opposite of cascade #1)

66
Q

How does Gαt signal?

A

by activating PDE instead of inhibiting AC

Gαt is a closely related subunit to Gαi

67
Q

Cascade #3: G αq Signalling Pathway

How does this pathway signal?

A

by increasing DAG/IP3 levels

68
Q

Cascade #3: G αq Signalling Pathway

A
  1. Gαq-GTP binds to phospholipase C or PLC (primary enzyme)
  2. PLC synthesizes IP3 and DAG (second messengers)
  • IP3 regulates IP3-gated Ca2+ channels, which releases Ca2+ (second messenger)
  • Ca2+ enhances PKC, and targets intracellularly (effector proteins) – ie. ion channels, signalling proteins (calmodulin, vesicle proteins, transcription factors)
  • DAG binds and activates PKC
  • PKC phosphorylates many protein targets (effector proteins) – ie. some ion channels, SNAREs and vesicle proteins, other kinases and transcription factors (cascade)
  1. phosphatases (PPs) turn off the signal
    - block PKC
    - block IP3
    - remove phosphates from PKC targets
69
Q

What are some roles that Ca2+ can play in signal transduction?

A
  • second messenger – activating calmodulin, which then activates other regulator enzymes
  • regulator –directly binding and activating various regulator enzymes, including PKC and some forms of AC
  • direct effector – ie. ie. controlling synaptotagmin and gating Kca channel activity
70
Q

What is one of several mechanisms through which cells can elevate their [Ca2+]i?

A

g-protein signalling

71
Q

What is the source of the increases in [Ca2+]i during g-protein signalling?

A

extracellular or intracellular – from ER stores

72
Q

Does an increase in [Ca2+]i during g-protein signalling affect Vm?

A

when the release of Ca2+ ER stores is intracellular, there is no direct effect on Vm

73
Q

What mechanisms do intracellular calcium ions act through in biochemical cascades?

A
  • directly interacting with effector proteins or enzymes

- binding to transducer proteins which then activate other enzymes/proteins

74
Q

What is the reason why a neurotransmitter can have opposite effects depending on which metabotropic receptor it binds to?

A

because different subtypes couple to different alpha subunits

75
Q

What does the stimulatory alpha subunit subtype (Gαs) do to smooth muscle? To heart muscle?

A
  • causes smooth muscle relaxation – smooth muscle contractions are inhibited by cAMP, though they are stimulated by Ca2+
  • causes increase in heart muscle contraction
76
Q

What are some roles of G-βγ subunits?

A
  • important signalling roles in neuronal transduction pathways – once unbound from α subunit, βγ complex can act as a signalling molecule and mediate a variety of intracellular effects, including important effects on electrical signals
  • can bind and directly trigger opening of certain ion channels (typically K+ selective), changing Vm
  • can modify VG-Ca channel properties (typically raises their activation threshold – inhibits activation)
  • sometimes alter the activity of regulator enzymes
77
Q

What is the Neuron Doctrine?

A

direction of information flow through the nervous system is unidirectional (axon AP → neurotransmitter → dendritic EPSP)

78
Q

Does chemical synaptic transmission fit the Neuron Doctrine?

A

yes…

BUT you can find receptors on the presynaptic terminal in certain circumstances

79
Q

What are the 3 circumstances in which receptors are found on the presynaptic terminal?

A
  • axoaxonic synapses
  • autoreceptors
  • retrograde signals
80
Q

What are axoaxonic synapses?

A

synapses that make direct (one-way) contact between axon terminals

81
Q

Where are axoaxonic synapses found?

A

in many different neuronal circuits across different animal species (but are not as common as axodendritic or axosomatic synapses)

82
Q

What is the function of axoaxonic synapses? Do they use ionotropic or metabotropic receptors?

A
  • some are efficient inhibitory synapses using inhibitory ionotropic receptors
  • most are modulatory synapses that signal through metabotropic receptors – these can affect both VG-K and VG-Ca channels, and also lead to phosphorylation of active zone proteins such as SNAREs and docking proteins
83
Q

When axoaxonic synapses are modulatory and signal through metabotropic receptors, what can this affect?

A

can affect both VG-K and VG-Ca channels, and also lead to phosphorylation of active zone proteins such as SNAREs and docking proteins

84
Q

What are autoreceptors?

A

metabotropic receptors on a presynaptic terminal that respond to the same neurotransmitter released by that terminal

85
Q

What are autoreceptors usually (but not always)?

A

GPCRs coupled to Gi/o subtypes, and produce negative feedback on neurotransmitter release

ie. ACh-releasing terminals possess muscarinic ACh receptors (mAChRs)
ie. GABA releasing terminals express GABABRs

86
Q

What subunit signalling contributes to inhibition of neurotransmitter release by autoreceptors?

A

both α and βγ signalling

87
Q

What are retrograde signals?

A

ligands that are synthesized and released from the postsynaptic cell (or a glial cell)

88
Q

What is sensitive to retrograde signals?

A

sometimes presynaptic receptors are sensitive to these

89
Q

What are true examples of retrograde synaptic signalling?

A

some presynaptic metabotropic receptors

90
Q

Are retrograde messengers hydrophobic or hydrophilic?

A

hydrophobic

91
Q

When are retrograde messengers synthesized?

A

synthesized on demand, but synthesis is often triggered in response to metabotropic receptor activation by conventional neurotransmitters (ie. by increase in cAMP or Ca2+)

92
Q

What are cannabinoid receptors (CBs or CBRs)?

A

principal targets of cannabinoid drugs (THC, CBD)

  • in CNS, CBRs are GPCRs that are typically found on presynaptic terminals, and couple to Gαi/o subtypes

the best described examples of presynaptic receptors that receive ‘retrograde message’

93
Q

What are endocannabinoids?

A

endogenous molecules that activate cannabinoid receptors

two best known: anandamide, 2-AG

94
Q

What is THC?

A

cannabinoid agonist

95
Q

When are endocannabinoids synthesized?

A

synthesized by postsynaptic neurons in response to a rise in intracellular Ca2+ through VG Ca2+ channels, NMDARs, and/or αq mediated signalling

96
Q

What do endocannabinoids do once they’re synthesized?

A

diffuse through postsynaptic membrane and bind the CBRs located on the presynaptic terminal

97
Q

How do metabotropic neurotransmitter receptors signal?

A

by initiating intracellular biochemical signalling cascades (rather than by directly opening and closing ion channels)

98
Q

Do metabotropic responses trigger effects on membrane potential?

A

yes – by coupling intracellular signals (second messengers) to internally gated ion channel opening and closing

99
Q

What are metabotropic receptors? How do they act?

A

g-protein coupled receptors that mediate distinct cellular effects by activating different heterotrimeric g-protein-mediated cascades

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