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psc2002 > lecture 23 > Flashcards

lecture 23 Flashcards

1
Q

what are the ways protein kinases are activated by?

A

-cyclic GMP (activation of protein kinase G)
-increase in Ca2+ (PKC and Ca2+/calmodulin dependent PK)

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2
Q

what are the features of the cyclic GMP signalling pathway?

A

-GPCRs NOT involved
-cGMP generated by guanylyl cyclase (GC)

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3
Q

what are the two types of guanylyl cyclase?

A
  1. soluble form (sGC) - activated by nitric oxide
  2. plasma membrane bound form (pGC) -activated by small number of peptide agonists
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4
Q

what does cGMP do?

A

-binds to protein kinase G to activate it

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5
Q

what does PKG phosphorylate?

A

serine and threonine residues

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6
Q

what is cGMP broken down by?

A

cGMP dependent phosphodiesterases

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7
Q

how is NO produced?

A

made by enzyme nitric oxide synthase (NOS)
made by epithelial cells

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8
Q

what is the summary of NO pathway?

A

-NO gets into cell and activates the soluble GC to make cGMP
-goes on to activate PKG and phosphorylate target proteins to get a response

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9
Q

how is pGC used to produce cGMP?

A

-able to bind to a variety of peptides (ANP)
-activates GC to make cGMP pathway
-built in activation as no G proteins

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10
Q

how is nitric oxide used in health and disease?

A

-released from endothelial cells
-activates soluble GC
-vasodilatation and increases blood flow
-used to treat angina (chest pain caused by too little blood flow to heart)
-helps with blood pressure control

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11
Q

how is LPS (endotoxin) used in health and disease?

A

-gram negative bacteria gotten from systemic infection
-stimulates expression of iNOS (inducible NOS)
-causes excessive NO production
-can lead to clinical shock as severe drop in BP- gets so low the body shuts down resulting in death

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12
Q

how is viagra (sildenafil) used in health and disease?

A

-type 5 cGMP PDE inhibitor
-produces smooth muscle relaxation in certain tissues
-treats erectile problems and pulmonary hypertension

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13
Q

how is CFTR used in health and disease?

A

-in intestine
-heat stable enterotoxin from E.coli
-switches on pGC
-cGMP activates PKG which phosphorylates CFTR
-overstimulation of cells
-cholera toxin - irreversible changes
-leads to secretory diarrhoea

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14
Q

what are the 3 groups of protein kinase C?

A

-conventional (need increase in calcium and bind to lipids to be activated)
-novel
-atypical

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15
Q

what is the structure of protein kinase C?

A

single polypeptide
regulatory and catalytic domains
11 different isoforms
require phospholipid binding to be active

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16
Q

what is a pseudo substrate motif (PS)?

A

-in R domain
-keeps kinase inactive by occupying the substrate binding site on the C4 domain
-keeps in OFF position until needed to be activated

17
Q

what is the process of the activation cycle for cPKC?

A
  1. Ca2+ binds to C2 domain, PKC translocates to plasma membrane - binds to DAG via C1 domain
  2. causes PS motif to disengage from catalytic (C4) domain, so substrates can bind and get phosphorylated
18
Q

what chemicals can artificially activate?

A

phorbol esters -plant alkaloids that are tumorigenic
bind directly to PKC

19
Q

what are the two broad types of Ca2+/calmodulin dependent protein kinases?

A
  1. have narrow substrate specificities eg. phosphorylase kinase only phosphorylates phosphorylase
  2. with broad substrate specificities eg. multifunctional CaM kinase ll (CaMKll)-phosphorylates many
20
Q

what are the functions of CaMKll?

A
  1. associates with NMDA receptors
  2. enhances InsP3 formation
  3. plays role in frequency decoding of calcium signals
  4. phosphorylates phospholamban to control pumping of SERCA2 pump
21
Q

what do protein phosphatases do (PP)?

A

-remove phosphate groups from phosphorylated proteins (serine/threonine/tyrosine)

22
Q

what are the 4 major classes of Set/Thr protein phosphatases?

A

1, 2A, 2C = broad and overlapping substrate specificity
2B (CaN) = restricted specificity - requires Ca2+/CaM for activity

23
Q

what are PPs regulated by?

A

inhibitory proteins

24
Q

what are the chemical inhibitors of protein phosphatases?

A

-okadaic acid = blocks PP1 and PP2A
-cyclosporin A = specific for calcineurin (2B) - used for immunosuppression via effects on T cells

25
Q

what is okadaic acid?

A

-toxin produced by algae
-accumulate in marine sponges and shellfish
-when ingested cause diarrhetic shellfish poisoning (DSP)

26
Q

what are the symptoms of diarrhetic shellfish poisoning (DSP)?

A

severe and acute diarrhoea, vomiting and nausea

27
Q

what is acute diarrhoea caused by?

A

effects on:
1. tight junctions - get increased paracellular permeability
2. more active CFTR - promotes fluid loss from GI tract

28
Q

what is OA an inhibitor of?

A

PP1 and PP2A

29
Q

what is the role of phosphatase inhibitory proteins?

A

eg. glycogen breakdown
-GPCR and PKA phosphorylates phosphorylase kinase which switches it on
-this phosphorylates phosphorylase which switches it on
-then glycogen broken down to form glucose and energy
-glycogen synthase (inhibitory) also activated by protein kinase A

30
Q

how does PKA activate phosphatase inhibitory proteins?

A

-inactive phosphatase inhibitory protein gets phosphorylated by PKA
-can bind to protein phosphatase and inhibit activity
-rise in cAMP favours glycogen breakdown

31
Q

what is the synergy between cAMP and Ca2+ pathway in skeletal muscles?

A

-depolarisation of NMJ linked to release ca2+ in skeletal muscle
-contraction initiated
-glycogen breakdown promoted as need oxygen for energy to contract muscles
-produces glucose through glycolysis
-Ca2+ also affects phosphorylase kinase

32
Q

what is the structure of phosphorylase kinase?

A

-4 subunits -> complex structure
-delta subunit is calmodulin (increases calcium sensitivity)
-gamma subunit is the catalytic subunit
-alpha and beta are regulatory subunits that are phosphorylated by protein kinase A

33
Q

what does phosphorylation of phosphorylase by PKA cause?

A

increase in calcium sensitivity

psc2002 (15 decks)

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