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ICPP > L7- Effector mechanisms > Flashcards

L7- Effector mechanisms Flashcards

1
Q

Outline the order of the intracellular signalling cascade

A
  1. Ligand binding to GPCR
  2. G-protein activation (different alpha subunits- Gs, Gi and Gq)
  3. Activation of effector proteins (can be enzyme or ion channel)
  4. If stimulatory, generation of IC 2nd messenger (cAMP, IP3, DAG and Ca2+)
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2
Q

What are the 3 different subtypes of alpha subunits of G-proteins and what is their effect?

A
  1. Gs: stimulatory-> activates adenylyl cyclase –. atp into camp - Pka
  2. Gi: inhibitory–> inhibits adenylyl cyclase- lowers Camp- lowers pka activity
  3. Gq: tends to be stimulatory –> activates phospholipase C (PLC) – converts PIP2 into IP3 and DAG– increase Ca2+ and activated PKCS
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3
Q

List the names of effectors you need to know

A

ENZYMES:

  1. Adenylyl cyclase enzyme: ATP –> cyclic AMP (cAMP)
  2. Phospholipase C: PIP2 –> IP3 + DAG
  3. PI3K: PIP2 –> PIP3

ION CHANNELS:

  1. Voltage-operated Ca2+ channels (VOCCs)
  2. G-protein regulated inwardly rectifying K+ channels (GIRKs)
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4
Q

Outline how Adenylyl cyclase can be regulated

A
  1. Stimulated
    - Agonist binds to GPCR
    - G-protein activated
    - Gα-s subunit binds to adenylyl cyclase enzyme and is stimulated
    - catalyses ATP into cyclic AMP (2nd messenger)
    - this activates cAMP dependent protein kinase (PKA) to phosphorylate target proteins
  2. Inhibited:
    - agonist binds to GPCR
    - G-protein activated
    - Gα-i subunit binds to adenylyl cyclase enzyme and is inhibited
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5
Q

What is Adenylyl cyclase and what is its function?

A
  • integral plasma membrane protein

- when activated, catalyses conversion of ATP into cyclic AMP (cAMP)

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6
Q

a) What are 2nd messengers?

b) Types and functions

A

a) Second messenger, molecule inside cells that acts to transmit signals from a receptor to a target

b) 1. Cyclic AMP (cAMP): interacts with cAMP dependent protein kinases (PKA) which will phosphorylate target proteins
2. IP3: soluble and it binds to IC Ca2+ receptors on ER to allow Ca2+ to leave ER lumen and enter cytoplasm, Ca2+ then activate Ca2+ sensitive protein kinases (PKC’s)
3. DAG: bound to membrane, interacts with protein Kinase C’s (PKC’s) which then phosphorylate other molecules

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7
Q

How does cAMP do its job?

A
  • cAMP is a 2nd messenger that will interact with cyclic-AMP dependent protein kinase (PKA)
  • PKA has a regulatory and catalytic subunit
  • cAMP binds to the regulatory subunit of PKA which leads to a conformational change and activates catalytic subunit
  • protein can now phosphorylate other proteins by removing a pO4 from ATP and adding it to a serine residue on the target protein
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8
Q

Outline how phospholipase C is regulated?

A
  • Agonist binds to GPCR
  • G-protein activated
  • Gα-q subunit binds to PLC and it is stimulated
  • Catalyses conversion of PIP2 into IP3 + DAG (2nd messengers)
  • IP3 interacts with IC Ca2+ receptors on ER, allowing Ca2+ to leave lumen and enter cytoplasm
  • increases IC Ca2+, Ca2+ binds to ca2+ sensitive protein kinases (PKCS)
  • DAG stays in membrane and interacts with PKCs with ca2+ to activate
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9
Q

QISS QIQ is a mnemonic to remember the type of receptors.

What is the group QISS and what is the group QIQ referring to?

A

a) QISS: Sympathetic receptors–> adrenoceptors
- Alpha 1 and Alpha 2: located in arteries, stimulated by adrenaline/noradrenaline causing arteries to contract, increasing BP
- Beta-1-adrenoceptors: located in heart, stimulated by adrenaline/noradrenaline, increase HR
- Beta-2-adrenoceptors: located in bronchioles of lungs and arteries of skeletal muscles: adrenaline/noradrenaline causing dilation of bronchioles (more air in and out) and of skeletal muscle vessels (recieve more blood)

b) QIQ: Parasympathetic receptors –> muscarinic receptors
- M1- Muscarinic receptor: located in CNS/brain, ACh stimulates cognition
- M2-Muscarinic receptor: located in heart, ACh inhibitory effect to slow down HR
- M3-Muscarinic receptor: located in smooth muscle and glands, ACh stimulatory effect, contraction of smooth muscles + gland secretion

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10
Q

Signal amplification is a key feature of cell signalling.

a) why
b) outline what this is

A

a) An extracellular stimulus may only be a few molecules and is not very big and hence amplification needs to occur to generate an intracellular response
b) 1. Activated receptor can cause GTP/GDP exchange on more than one G-protein
2. Activated G subunit can activate multiple effector molecules
3. Effector molecules act catalytically and hence will catalyse production of lots and lots of 2nd messengers
4. these then activate their targets

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11
Q

Outline the signalling pathways involved in inotropy of the heart

A
  • circulating adrenaline and sympathetically released noradrenaline can activate B1-adrenoceptors in heart, - these activate adenylyl cyclase via Gs-GTP,
  • this increases cAMP concs
  • which then activates cAMP dependent protein kinases (PKA’s)
  • which phosphorylate voltage operated calcium channels (VOCCs)
  • increase in Ca2+ conc increases force of heart contraction (positive inotropy)
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12
Q

Where are alpha adrenoceptors located?

A

Arteries

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13
Q

Where are Beta-1-adrenoceptors located?

A

Heart

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14
Q

Where are Beta-2-adrenoceptors located?

A

Bronchioles of lungs and arteries of skeletal muscles

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15
Q

Where are:
A) M1
B) M2
C) M3

muscarinic receptors located?

A

a) CNS and brain
b) Heart
c) located in smooth muscles and glands

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16
Q

a) What ligand targets adrenoceptors?

b) what ligand targets muscarinic receptors?

A

a) Noradrenaline

b) ACh

17
Q

a) Where are adrenoceptors found?

b) Where are muscarinic receptors found?

A

a) Sympathetic system

b) Parasympathetic system

18
Q

Outline the signalling pathways involved in:

a) Arteriolar vasoconstriction
b) Bronchoconstriction

A

a) - Sympathetically released Noradrenaline binds to alpha1-adrenoceptors, activating PLC via the Gq-GTP g protein, IP3 increases Ca2+ conc which binds to PKC, DAG binds to PKC –> phosphorylation occurs and constriction of arterioles occur
b) Parasympathetically released ACh can bind to smooth muscle M3-muscarinic receptors, activating the same pathway above to cause bronchoconstriction

19
Q

Outline the signalling pathways that modulate neurotransmitter release
- use an example with morphine

A
  • G protein-coupled receptors located pre-synaptically can influence the release of neurotransmitters at the synapse
  • morphine can bind to presynaptic GPCR u-opoid receptor
  • G-protein activation
  • G-beta-gamma subunits interact with voltage operated Ca2+ channels (VOCCs) to reduce entry of Ca2+ through these channels
  • decrease in Ca2+ influx inhibits the release of neurotransmitter from the pre-synaptic terminal
20
Q

What are the 3 properties of signal transduction?

A
  1. Diversity: there is a diverse range of stimuli, receptors, G-proteins and effectors
  2. Specificity: specific ligand receptor interactions, specific G-protein alpha subunits recruited, which are coupled to particular effector pathways
  3. Amplification: gain control on all signalling pathways, allowing relatively small changes in EC signals to elicit significant changes in cellular behaviour
21
Q

a) What are the ways in which whole body Ca2+ homeostasis is regulated?
b) How are these processes in a controlled?

A

a) - intestinal ca2+ uptake
- ca2+ reabsorption in kidneys
- bone calcium regulation (bone turnover)

b) Endocrine control:
- Ca2+-sensing receptors in parathyroid gland
- parathyroid hormone
- 1,25-dihydroxyvitamin D3
- Calcitonin

22
Q

What are the Ca2+ concentrations:

a) Intracellular
b) Extracellular
c) Inside ER/SR

A

a) LOW: 1 X10^-7 M
b) HIGH: 1-2 x 10^-3 M
c) 2-3 x 10 ^ -4 M

23
Q

Why are changes in IC Ca2+ concentration so important?

A

Regulate a wide range of processes such as:

  • muscle contraction (smooth, skeletal and heart)
  • Neurotransmission/stimulus-secretion coupling
  • fertilisation
  • cell death (apoptosis, necrosis)
  • regulation of metabolism
  • learning and memory
24
Q

How is the low IC ca2+ concentration maintained?

A
  1. Relative impermeability of the plasma membrane to Ca2+
  2. Ca2+ buffer proteins
  3. Pumps and transporters that move Ca2+ out of the cytoplasm: PMCA (plasma membrane Ca2+ ATPase) and SERCA: (SR/ER Ca2+-ATPase, moves into ER), NCX in heart (Na+, Ca2+ exchanger)
25
Q

What is the importance of having a low intracellular calcium concentration?

A
  • it means that a slight change in its conc will cause an effect in the cell- vesicle fusion w membrane to release neurotransmitter
  • muscle contraction
  • use calcium as a second messenger in the cell to cause things to happen
26
Q

Mechanisms that increase IC ca2+ to generate signals

A
  • Open ligand gated ion channels
  • Voltage operated Ca2+ channels (respond to change in membrane polarisation
  • Ca2+ movement out of the Endoplasmic/sarcoplasmic reticulum: IP3 Receptor (IP3 is a 2nd messenger, binds to receptor, releases Ca2+) AND CICR ryanodine receptor (calcium induced calcium release)
27
Q

What is PIP2?

A

A phospholipid in the plasma membrane

28
Q

What is inotropy?

A

change in force of contraction of the heart

29
Q

Outline the main steps involved in “Calcium-induced Calcium release”

A
  • Involved ryanodine receptors
  • in muscle sarcoplasmic reticulum
  • depolarisation of the t tubules causing the voltage gated calcium channels to open leading to an influx of calcium, calcium binds to Ryanodine receptors which results in a very large synchronous outwards flux of SR ca2+ into the sarcoplasm (muscle cytoplasm)
30
Q

Describe the role of calcium buffers

A
  • aim is to lower IC calcium conc
  • as ca2+ moves through cytoplasm, its rate of diffusion is slowed due to presence of buffer proteins that smooth out and dampen the rapid entry of calcium
  • bind to calcium
  • calbindin and parvalbumin
31
Q

What are calcium sensors and what do they do?

A
  • they transduce calcium signals to other proteins
  • they are calcium binding proteins that will go on to regulate other proteins
  • ## calmodulin can bind to 4 ca2+ and have a conformational change

ICPP (8 decks)

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