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BMS2002 > L14 > Flashcards

L14 Flashcards

1
Q

AC is inhibited and stimulated via G protein

A

True

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2
Q

what subunit is different in G protein that stimulates AC

A

alpha s – stimulates AC
alpha i – inhibits AC

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3
Q

what receptors are coupled to Gs proteins

A

b-adrenoceptors

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4
Q

what receptors are coupled to Gi proteins

A

a2 adrenoceptors

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5
Q

how does the cholera toxin work

A

Signalling via G proteins depends upon exchange of GDP for GTP

Active a subunit has GTP bound

Hydrolysis of GTP leads to inactivation

Cholera toxin (CTx) acts on as subunit and causes ADP-ribosylation

This prevents hydrolysis of GTP

Causes persistent activation of a subunit

In colon causes activation of PKA-dependent Cl- channels and “secretory diarrhoea”

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6
Q

what is lost from the body in cholera

A

Na

Cl

water

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7
Q

how does Pertusiss toxin work

A

Pertussis toxin acts on ai subunits

In this case locks subunit into inactive configuration

Prevents activation by receptors

Prevents inhibitory control over AC / PKA

Again leading to increased levels of cAMP and PKA

In airway leads to symptoms of whooping cough

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8
Q

what are the features of Gq

A

G proteins containing aq11 subunits allow hormones / neurotransmitters to activate amplifier enzyme Phospholipase C (PLC)

Underlies autonomic effects of acetylcholine (eg salivary secretion, bronchial smooth muscle contraction)

Histamine H1 receptor responses (G.I. smooth muscle contraction, allergies etc.)

Responses due to increased internal Ca2+

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9
Q

ACh also activates Muscarinic receptor “metabotropic receptor”

A

true

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10
Q

muscarinic receptors dont bind nicotine

A

False

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11
Q

Muscarinic receptors are Gq/Gi coupled receptors

A

true

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12
Q

what muscarinic receptors are Gq coupled

A

1,3, and 5

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13
Q

what muscarinic receptors are Gi coupled

A

2 and 4

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14
Q

Gq proteins second messengers are products of phosphoinositide breakdown

A

True

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15
Q

how does Gq work

A

Gq proteins stimulate phospholipase C (PLC)

PLC cleaves PIP2,a membrane phospholipid, into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG)

IP3 is the water soluble part of PIP2 and travels through the cytosol to stimulate
Calcium release from ER

DAG remains in the membrane (hydrophobic part) where it recruits Protein Kinase C (PKC)

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16
Q

IP3 is a second messenger that stimulates Calcium release from ER

A

True

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17
Q

how does IP3 stimulates Calcium release from ER

A

Since IP3 is hydrophilic it enters the cytoplasm

Binds to receptors on ER and promotes release of stored Ca2+

Also promotes Ca2+ influx from extracellular fluid by a mechanism that is less clear

Resultant increase in intracellular free Ca2+ promotes cellular responses

18
Q

what are the features of calcium mediated Intracellular responses

A

Mediated by Ca2+ -binding proteins

Calmodullin (CaM) is the most important

Each CaM binds 4 Ca2+ ions

Ca2+-CaM complex activates PDE (the enzyme that degrades cAMP)

Importantly, Ca2+-CaM complex activates
CaM kinases (CaMKs)

CaMKs phosphorylate Serine and Threonine residues on a number of substrate proteins

CaMKs are involved in smooth-muscle contraction.

α1 adreno-receptor is a Gq coupled protein receptor which mediates vascular smooth muscle contraction by increasing intracellular free Ca2+ activating CAMKs (vasoconstriction)

19
Q

what are the effects of DAG

A

DAG is hydrophobic and so remains in the plasma membrane

Presence of DAG increases the activity of Ca2+-dependent protein kinase

Evokes cellular responses by phosphorylating other proteins. The most important one is proteins kinase C (PKC)

PKCs can potentiate the effects of IP3

Mediates desensitization (cf b-ARK)

Regulates cell shape, cell proliferation and transcription factor activity

PKC also activate proteins regulating cell shape, cell proliferation and transcription factors

20
Q

what are the effects of a1-adrenoceptor
on blood pressure

A

It causes vascular smooth muscle tone contraction (‘vasoconstriction’)

via Gq-PLC-IP3-CaMK

Makes blood pressure to increase

21
Q

what are the effects of beta 2-adrenoceptor
on blood pressure

A

Cause relaxation of vascular smooth muscle (‘vasodilation’)

via Gs-cAMP-PKA

Makes blood pressure to decrease

22
Q

just adrenergic receptors can cause smooth muscle contraction

A

false

23
Q

what are the features of H1 histamine receptor

A

A Gq protein coupled pathways important in Asthma as it causes smooth muscle contraction in the airways (broncospasm)

24
Q

give 2 receptors that are linked to a Gi protein

A

alpha 2 adrenergic receptor

M2 muscarinic receptor

25
Q

what are the types of enzyme linked receptors

A

Receptor guanylyl cyclases

Receptor serine/threonine kinase

Receptor tyrosine-kinase

Tyrosine kinase-associated receptors

Receptor tyrosine phosphatase

26
Q

describe Receptor Guanylyl Cyclase

A

Contain 2 Guanylyl Cyclase domains which convert GTP to cGMP. cGMP activates downstream kinases

27
Q

what is the Mechanism of signalling of Receptor Guanylyl Cyclase

A
  1. Binding of ANP induces a conformational change in the receptor that causes receptor dimerization and activation.
  2. The Guanylyl cyclase activity of the receptor generates cGMP.
  3. Increased concentrations of cGMP activates other signalling molecules determining the response
  4. Example of response: Atrial natriuretic peptide (ANP) relax vascular smooth muscle and dilate blood vessels (vasodilation)
28
Q

describe Receptor Serine/Threonine kinases

A

Contain Serine-Threonine kinase domains which phosphorylate target proteins (similar to PKA)

29
Q

what is the Mechanism of signalling of Receptor Serine/Threonine kinases

A
  1. first messenger binds to receptor Type II
  2. Receptor Type I then binds forming a ternary complex with Type II and first messenger.
  3. Type II receptor phosphorylates Type I, activating the Ser-Thr Kinase activity of Type I
  4. Type I then phosphorylate target proteins (re SMAD proteins)
  5. Example of response: TGFbeta mediated cell proliferation
30
Q

what do SMAD proteins do

A

regulate transcription of target genes

31
Q

describe Receptor Tyrosine Kinases (RTKs)

A

Contain tyrosine kinase domains which phosphorylate themselves/other proteins.

32
Q

what is the mechanisms of signaling of Receptor Tyrosine Kinases (RTKs)

A
  1. Binding of 2 molecules of insulin causes the receptor to dimerise.
  2. Once the receptors dimerise, then they use their cytoplasmic tyr kinase activity to phosphorylate each-other at multiple tyrosine residues creating “phosphotyrosine motifs”.
  3. These motifs recruit intracellular signalling molecules leading to the response
  4. Example of response: insulin mediated glucose uptake and storage in liver and muscles
33
Q

give an example of RTKs signal transduction

A

MAP kinase signalling pathway

34
Q

what happens in MAP kinase signalling pathway

A

RTKsactivateRas

Anadaptorproteindocksonaparticularphosphotyrosineontheactivatedreceptor

TheadaptorrecruitsaRasguaninenucleotideexchangefactor(Ras-GEF)thatstimulatesRastoexchangeitsboundGDPforGTP

TheactivatedRasproteincannowstimulateseveraldownstreamsignalingpathways

RasactivatesMAP-kinase kinase kinase

MAP-kinase kinase kinaseactivates MAP-kinase kinase

MAP-kinase kinase activates MAP-kinase

MAP-kinase can change protein activity or gene expression

35
Q

how is Ras anchored to the inside of the plasma membrane

A

Rasproteincontainsacovalentlyattachedlipidgroup

36
Q

describe Tyrosine kinase-associated receptors

A

The receptors do not contain kinase domains. Instead, tyrosine kinase proteins are associated non-covalently with the cytoplasmic domains

37
Q

what is the mechanism of signaling of Tyrosine kinase-associated receptors

A

1) Binding of first messenger to the receptor, induce a conformational change that cause dimerization of the receptor

2) The dimerization causes activation of the associated Tyr kinases (E.G. JAK2).

3) These kinases then phosphorylate tyrosine residues on both themselves and the receptor, creating “phosphotyrosine motifs” (Like the Tyr-Kinase receptors).

4) These motifs recruit intracellular signalling molecules leading to the response (re STAT proteins)

5) Example of response: cytokines signalling pathways (IL-6 acute phase response)

38
Q

describe Receptor tyrosine phosphatase

A

the receptors contain tyrosine phosphatase domains and remove Tyr residues to deposphorylate target proteins (For instance Tyr residues created by Tyr kinase receptors signaling)

39
Q

what is the mechanism of signaling in Receptor tyrosine phosphatase

A
  1. 1st messenger binding to the receptor inducing a conformational change that activates the Tyr phosphatase activity of the receptor.
  2. Target proteins are dephosphorylated by Tyr phosphatase activity
  3. This causes phosphorylation of downstream proteins (for example Lck and Fyn)
  4. Response example: CD45 induces the maturation of lymphocytes via binding to this receptor
40
Q

which receptors do not contain intrinsic enzymatic activity

A

Tyrosine kinase associated receptor

41
Q

which receptors involve dephosphorylation of target protein rather than phosphorylation

A

receptor tyrosine phosphatase

42
Q

what receptor increase cGMP

A

receptor guanylyl cyclase

BMS2002 (14 decks)

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