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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?

A

-PKA

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
Q

Which important receptors are linked to Gas?

A
  • B-adrenoreceptors
  • D1-dopamine receptors
  • H2-histamine receptors
26
Q

Which important receptors are linked to Gai?

A
  • a2-adrenoreceptors
  • D2-dopamine receptors
  • H-opiod receptors
27
Q

Describe the activation of PKA

A
  • 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
Q

What does PKA target on effectors?

A

-Serine/threonine residues

29
Q

What is the main function of PLC?

A

-Cleavage of PIP2 into IP3 and DAG

30
Q

What are IP3 and DAG?

A

-Second messengers

31
Q

What is the function of IP3?

A

-Bind to IP3 receptors on SR opening a ligand-gated Ca channel, allowing Ca to enter cell down its conc gradient

32
Q

How can PKC be activated?

A
  • Increasing intracellular calcium

- Interaction with DAG

33
Q

Which Gprotein activates PLC?

A

-Gaq

34
Q

What are some cellular changes regulated by PLC?

A
  • Vascular, GI tract and airway smooth muscle contraction
  • Mast cell degranulation
  • Platelet aggregation
35
Q

Which GPCRs associate with Gaq?

A
  • a1-adrenoreceptors

- M1-muscarinic receptors

36
Q

Describe the activation and function of cGMP phosphodiesterase, in relation to the eye?

A
  • 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
Q

How is signal amplification achieved?

A

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
Q

What mechanisms control deactivation of signal transduction from GPCRs?

A

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
Q

How is chronotropy of the heart decreased through Gproteins?

A
  • 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
Q

How is inotropy of the heart increased through GPCRs?

A
  • 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
Q

How is arteriolar vasoconstriction activated through GPCRs?

A
  • 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
Q

How is bronchoconstriction activated through GPCRs?

A

-Ach acts on M3-muscarinic receptor which associates with Gaq -> PLC-> IP3-> increased intracellular calcium -> contraction of smooth muscle

43
Q

How can neurotransmitter release be modulated through u-opioid receptor?

A
  • 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
Q

B-adrenoreceptors are coupled to which Gprotein?

A

-Gas

45
Q

a-adrenoreceptors are coupled to which G-protein?

A
  • a1 coupled to Gaq

- a2 coupled to Gai

46
Q

-Muscarinic ach receptors are coupled to which Gproteins?

A
  • M1, M3 and M5 coupled to Gaq

- M2 and M4 coupled to Gai

47
Q

Describe a pneumonic for remembering receptors and their associated G proteins

A

Qu - a1 Q - M1
I - a2 I - M2
S - b1 Q - M3
S - b2

Membranes and Receptors (13 decks)

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