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Membranes and Receptors > Session 7 - Receptor-Effector signalling > Flashcards

Session 7 - Receptor-Effector signalling Flashcards

1
Q

Name the three superfamilies of cell surface receptor

A
  • Ligand-gated
  • Receptors with intrinsic activity
  • GPCR
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2
Q

How do GPCRs alter cellular functions?

A

-Use Guanine nucleotide binding proteins (Gproteins) to activate/inhibit second-messenger generating enzymes or ion channels which then alter cellular function

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3
Q

What is signal transduction?

A

-The transfer of a signal produced by the binding of an extracellular ligand to the target effector intracellularly to generate the desired response

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4
Q

What is the basic structure of GPCRs?

A
  • Single polypeptide chain with 7 TMDs
  • Extracellular N terminal and intracellular C terminal (most)
  • 2 ligand binding sites –> Some onto N terminal and 2-3 TMD cleft
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5
Q

How is the signal passed from the receptor to the G protein?

A

-Agonist-binding to GPCR activates the receptor and causes a conformational change which allows interaction and activation of the G protein

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6
Q

Why are G proteins described as heterotrimeric?

A

-Made of 3 subunits a,b,g

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7
Q

What are the two functional units of a G-protein?

A
  • a

- bg

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8
Q

Which subunit of a G protein has a guanine binding site?

A

-a

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9
Q

Describe activation of the G protein

A
  • In basal state Ga is bound to bg and GDP
  • Upon activation, GDP leaves the subunit and GTP binds in its place -> (GDP/GTP exchange)
  • The binding of GTP to Ga decreases Ga affinity for the receptor and Gbg causing dissociation
  • Ga and Gbg are not free to interact with effectors
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10
Q

What facilitates GDP-GTP exchange?

A

-The receptor as it acts as a guanine nucleotide exchange factor

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11
Q

How is Gprotein signalling terminated?

A
  • Ga has an intrinsic GTPase which slowly hydorlyses GTP to GDP
  • Ga-GDP has increased affinity for Gbg and the heterotrimeric complex is reformed and becomes inactive, awaiting receptor activation
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12
Q

What determines the magnitude of the transduction from GPCRs?

A

-The timer function of GTPase of Ga which can be controlled by other proteins (RGS protein)

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13
Q

How is there a large range of diversity amongst GPCRs?

A

-20Ga, 5Gb and 12+Gg which vary in combinations producing over 1000 possible combinations

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14
Q

With a huge range of diversity, what ensures specificity amongst GPCR signalling?

A

-Each GPCR has preferential interactions with specific types f G proteins, determined mainly by Ga type

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15
Q

What is the effector of Gas?

A

-Activates adenyl cyclase=increased cAMP

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16
Q

What is the effector of Gai?

A

-Inhibits adenyl cyclase=decreased cAMP

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17
Q

What is the effector of Gaq?

A

-Activates phospholipase C= increased IP3 and DAG, regulates PKC

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18
Q

What is the effector of Gat?

A

-cGMP phosphodiesterase

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19
Q

How does cholera toxin work?

A

-Contains ADP-ribosyltransferase activity which adds an ADP-ribosyl group derived from NAD+ to Gas which inhibits GTPase activity of Gas = constitutively active

20
Q

How does whooping cough occur?

A

-Pertussin toxin from bordella pertussis contains ADP-ribosyltransferase activity which modifies Gai to prevent receptor association and Gai protein activation

21
Q

Give an example of GPCR signalling to activate and inhibit AC using the same ligand

A

-NA can act on B2-adrenoreceptors to activate AC via Gas or acts on a2-adrenoreceptors to inhibit AC via Gai

22
Q

What is the function of AC?

A

-Hydrolyse cellular ATP to generate cAMP

23
Q

What enzyme does cAMP regulate?

24
Q

What cellular responses does PKA regulate? (give a few examples)

A

-Glycogenolysis + gluconeogenesis
-Lypolysis
-Relaxation of smooth muscle
Positive inotropic/chronotropic effects in the heart

25
Which important receptors are linked to Gas?
- B-adrenoreceptors - D1-dopamine receptors - H2-histamine receptors
26
Which important receptors are linked to Gai?
- a2-adrenoreceptors - D2-dopamine receptors - H-opiod receptors
27
Describe the activation of PKA
- 2 regulatory domains sit in the active sites of 2 catalytic domains - Catalytic domains have intrinsic protein kinase activity - cAMP binds to regulatory units causing dissociation and activation as active sites are now free
28
What does PKA target on effectors?
-Serine/threonine residues
29
What is the main function of PLC?
-Cleavage of PIP2 into IP3 and DAG
30
What are IP3 and DAG?
-Second messengers
31
What is the function of IP3?
-Bind to IP3 receptors on SR opening a ligand-gated Ca channel, allowing Ca to enter cell down its conc gradient
32
How can PKC be activated?
- Increasing intracellular calcium | - Interaction with DAG
33
Which Gprotein activates PLC?
-Gaq
34
What are some cellular changes regulated by PLC?
- Vascular, GI tract and airway smooth muscle contraction - Mast cell degranulation - Platelet aggregation
35
Which GPCRs associate with Gaq?
- a1-adrenoreceptors | - M1-muscarinic receptors
36
Describe the activation and function of cGMP phosphodiesterase, in relation to the eye?
- In the dark, levels of cGMP sufficient to open ion channels allowing Ca and Na to enter - Gat becomes activated by a photon of light - Activated Gat activates cGMP phosphodiesterase which breaks down cGMP -> channel closure and membrane hyperpolarisation - Alters the signal input to CNS
37
How is signal amplification achieved?
1) Activted GPCR causes GDP/GTP exchange on multiple Gproteins 2) Activates Ga-GTP/Gbg activates multiple effectors 3) Effector molecules act catalytically ie 1 activates 100-1000s 4) Cellular targets of second messengers are often enzymeswhich act catalytically causing an enzyme cascade
38
What mechanisms control deactivation of signal transduction from GPCRs?
1) Agonist-receptor dissociation 2) Activated GPCr becomes phosphorylated preventing activation of further G proteins (receptor desinsitization) 3) GTPase of a-GTP 4) Intrinsic enzyme inhibitors of effector molecules
39
How is chronotropy of the heart decreased through Gproteins?
- Ach released from parasympathetic NS - acts on M2-muscarinic receptors - Leads to the opening of K+ channels by Gbg causing hyperpolarisation and increased K+ conductance should increase HR but.... - Decreased cAMP due to inhibition of AC by Gai - Decreased activation of HCN channels -> HR slows
40
How is inotropy of the heart increased through GPCRs?
- Increased sympathetic innervation -> NA and A activates B-adrenoreceptors - > Gas dissociates and activates AC -> increased cAMP - > Increased cAMP increases PKA activation - > PKA phosphorylates Ca channels causing then to open and increase intracellular Ca during plateau phase - B-adrenoreceptors also cause Increased SR uptake of Ca and increase sensitivity of contractile machinery to Ca
41
How is arteriolar vasoconstriction activated through GPCRs?
- Increased sympathetic activity = increased NA - NA acts on a1-adrenoreceptors on smooth muscle which associate with Gaq - Gaq activates PLC -> cleaves PIP2 to IP3 and DAG - IP3 causes Ca release from SR -> initiates contractile response
42
How is bronchoconstriction activated through GPCRs?
-Ach acts on M3-muscarinic receptor which associates with Gaq -> PLC-> IP3-> increased intracellular calcium -> contraction of smooth muscle
43
How can neurotransmitter release be modulated through u-opioid receptor?
- Pre-synaptoc u-opiod receptors can be stimulated by endogenous opiod (encephalin) or by analgesic such as morphine - GPCR associated with Gai; activated Gai which dissociate from Gbg - Gbg interact with VOCCs and reduce entry of Ca2+ - >decrease in Ca2+ influx to synaptic bouton inhibits the release of neurotransmitter
44
B-adrenoreceptors are coupled to which Gprotein?
-Gas
45
a-adrenoreceptors are coupled to which G-protein?
- a1 coupled to Gaq | - a2 coupled to Gai
46
-Muscarinic ach receptors are coupled to which Gproteins?
- M1, M3 and M5 coupled to Gaq | - M2 and M4 coupled to Gai
47
Describe a pneumonic for remembering receptors and their associated G proteins
Qu - a1 Q - M1 I - a2 I - M2 S - b1 Q - M3 S - b2

Membranes and Receptors (13 decks)

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