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Y1 - ICPP > Lecture 13 - GPCRs (Effector Mechanisms) > Flashcards

Lecture 13 - GPCRs (Effector Mechanisms) Flashcards

1
Q

What are some examples of effectors that can be activated by a GPCR alpha or Beta/Gamma subunit?

A

Adenylyl Cyclase (Know this pathway)
Phospholipase C (Know this pathway)

Don’t really need to know these:
PI3K
cGMP Phosphodiesterase (Found in eye)

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2
Q

What is the function of the effector enzyme Adenylyl cyclase?

A

Produce a Second messenger:
Produce cAMP (Cyclic AMP) from cellular ATP

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3
Q

What is the function of the effector enzyme Phospholipase C?

A

Produce second messengers:
Takes PIP2 and hydrolyses it to IP3 + DAG (Diacylglycerol)

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4
Q

What is the general function of effector enzymes stimulated by GPCR?

A

Produce second messengers

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5
Q

Where do all of the pathways for effector enzymes take place?

A

Constricted to the membrane (2 dimensionally)

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6
Q

What happens when an agonist binds to a Gs coupled receptor?

A

GDP for GTP exchange on the alpha subunit, causes the heterotrimeric subunit to split
Active Alpha s subunit DIRECTLY binds to Adenylyl Cyclase enzyme
STIMULATES Adenylyl cyclase (ATP —> cAMP)
INC [cAMP] in cell activates PKA
PKA can then go onto Phosphorylate other proteins

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7
Q

What is PKA?

A

Cyclic AMP-dependant protein kinase (PKA)

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8
Q

What happens when an agonist binds to a Gi protein coupled receptor?

A

GDP for GTP exchange on the alpha subunit, causes the heterotrimeric subunit to split
Active Alpha i subunit DIRECTLY binds to Adenylyl Cyclase enzyme
This inhibits the activation of Adenylyl cyclase
This prevents the formation of cAMP
The low level of cAMP inhibits activity of PKA (Cyclic AMP-dependant Protein Kinase)

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9
Q

What are the 2 parts to the enzyme Protein Kinase A (PKA/Cyclic AMP-Dependant Protein Kinase)?

A

Regulatory subunits
Catalytic subunits

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10
Q

How many regulatory subunits make up a PKA?

How many catalytic subunits make up a PKA?

A

2 regulatory subunits

2 catalytic subunits

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11
Q

What activates PKA?

How many of these molecules are needed to activate PKA?

Which part of PKA do these molecules bind to?

A

Cyclic AMP (cAMP)

4 molecules of cAMP activates PKA

2 molecules bind to each Regulatory subunit

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12
Q

What happens once Protein Kinase A (PKA) is activated? (In terms of subunits)

A

Conformational change to the regulatory subunits leads to the 2 catalytic subunits being released

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13
Q

What is the function of the 2 catalytic subunits released by an activated PKA?

A

Post translational modification (Phosphorylates proteins)

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14
Q

What type of G Protein Coupled Receptor regulates activity of Phospholipase C?

A

Gq coupled protein receptors

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15
Q

What type of membrane protein is Adenylyl cyclase?

A

Transmembrane

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16
Q

What type of membrane protein is Phospholipase C?

A

Integral protein = Only on inside of the membrane (Doesn’t span the whole membrane)

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17
Q

What is the function of IP3 as a second messenger?

A

Goes into cytoplasm and binds to IP3 receptors on Endoplasmic reticulum/sarcoplasmic reticulum membrane
Leads to release of the intracellular Ca2+ INC [Ca2+] in cytoplasm

18
Q

What is the function of the DAG second messenger?

A

Stays in membrane
Activates Protein Kinase C

19
Q

What 2 things stimulate the activity of Protein Kinase C (PKC)?

A

DAG
INC [Ca2+] intracellularly

20
Q

What happen when an agonist binds to a Gq Protein Coupled Receptor?

A

GDP for GTP exchange on the Alpha q subunit, causes the heterotrimeric subunit to split
Active Alpha q subunit DIRECTLY binds to Phospholipase C enzyme
Phospholipase C hydrolyses PIP2 to IP3 and DAG
IP3 goes to IP3 receptor on SR/ER triggering release of Ca2+ into cytoplasm from Intracellular store
DAG activates PKC
Ca2+ also activates PKC

20
Q

Why is signal amplification via G Protein Coupled Receptors important?

A

Allows for a small signal too cause a relatively large/significant cellular/physiological response

21
Q

Which part of the G-protein coupled receptor pathway does the main part of signal amplification occur?

A

When many cAMP molecules are produced (many second messengers)

22
Q

What is inotropy?

A

The strength of muscle contraction

23
Q

What G Protein Coupled receptor is involved in the pathway which increases the strength of heart muscle contraction?
(+ve inotropic effect)

A

B1 - adrenoceptors

Are Alpha s coupled

24
Q

What ion are we wanting to increase the intracellular concentration of in order to get a +ve inotropic effect in the heart?

A

Ca2+ (Calcium)

25
Q

What are the agonists that bind to the B1- Adrenoceptors in the heart to cause a +ve inotropic effect?

A

Adrenaline or noradrenaline

26
Q

What happens once adrenaline/noradrenaline binds to the Gs Coupled B1-Adrenoceptor in the heart (up to just before the SR is reached)?

A

GDP for GTP exchange on the Alpha s subunit, causes the heterotrimeric subunit to split
Active Alpha s subunit DIRECTLY binds to Adenylyl Cyclase enzyme
ATP —> cAMP
cAMP activates PKA
PKA Phosphorylates Voltage Gated Calcium Ion channels allowing more Ca2+ influx

27
Q

What happens once adrenaline/noradrenaline binds to the Gs Coupled B1-Adrenoceptor in the heart (as Ca2+ approaches the SR)?

A

Ca2+ binds to ryanodine receptor on SR
This receptor channel opens allowing Ca2+ to flood into cell from the SR
Increased levels of Ca2+ = stronger heart contraction

28
Q

What structure takes Ca2+ back up into the SR?

A

SERCA

29
Q

What is the receptor which is on vascular smooth muscle controlling vessel tone?

A

a1 - adrenoceptor

30
Q

What agonist binds to a1- adrenoceptors stimulating vasoconstriction?

A

Noradrenaline

31
Q

What receptor can ACh bind to and cause brochoconstriction?

A

M3 - Muscarinic receptors

32
Q

What type of G Protein Coupled Receptor protein (a1- adrenoceptor) is involved in mediating vasoconstriction of blood vessels?

A

Gq

33
Q

In mediating vasoconstriction what is the general role of IP3?

In mediating vasoconstriction what is the general role of PKC being activated?

A

Stimulate muscle contraction (Inc [Ca2+] intracellularly)

PKC ensures muscle contraction is maintained/continuos

34
Q

How does PKC ensure the muscle contraction is continuous in vasoconstriction?

A

PKC inhibits MLCP (Myosin Light Chain Phosphatase)

Myosin Light Chain Phosphatase dephosphorylates the myosin head inactivating it

So if MLCP is inactivated, the myosin head remains activated so continous muscle contraction can occur

35
Q

How does smooth muscle normally contract without the presences of PKC?

A

Ca2+ influx into cell
Ryanodine receptor leads to more Ca2+ released from SR (Ca2+ induced Ca2+ release)
Ca2+ binds to Calmodulin
Calmodulin activates MLCK
MLCK Phosphorylates light chain on myosin head activating it
Contraction Occurs
MLCP dephosphorylates myosin head Deactivating the myosin chain causing it to relax

36
Q

What type of G Protein Coupled receptor is important in the regulation of neurotransmitter release?

A

Opioid receptors (μ - opioid receptors)

37
Q

What channels do Opioid receptors affect to regulate neurotransmitter release?

What affect do these G Protein Coupled Receptors have on these channels?

A

Voltage Gated Calcium Channels

Inhibits these channels since μ- opioid receptor is a Gi coupled receptor

38
Q

What is an example of a drug that acts on μ- opioid receptor?

A

Morphine

39
Q

What happens when morphine binds to a μ- opioid receptor?
Is morphine an agonist or antagonist to the opioid receptor?
Which subunit is important?

A

GDP for GTP exchange happens on Alpha i subunit
The B/γ binds to the Voltage gated Ca2+ channel inhibiting it
Less Ca2+ influx into Pre-synaptic membrane
Less neurotransmitter released from membrane

40
Q

What is the overall effect of morphine causing less Ca2+ influx into the Pre-synaptic membrane?

A

Ca2+ binds to vesicles containing neurotransmitter stimulating them to release NT into the synaptic cleft

Less Ca2+ = Less NT in cleft = less post synaptic stimulation = LESS PAIN

Y1 - ICPP (23 decks)

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