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physiology and pharma > L5 - secondary messengers > Flashcards

L5 - secondary messengers Flashcards

1
Q

why is signal amplification useful?

A

can provide very sensitive responses to a small amount of primary messenger (efficient)

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2
Q

what does having multiple secondary messenger pathways allow

A
  • more complexity of signalling (and more efficient from a small amt of primary messenger) and graded responses
  • allows ligand to produce different responses by acting on different receptors
  • allows ligand to produce different effects when acting on the same ligand, but in different areas
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3
Q

give example where the same ligand acting on different receptors causes different effects

A

NA acting on B2 causes relaxation

NA acting on a1 of smooth muscle causes contraction

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4
Q

give an example where the same ligand acting on the same receptor in different locations causes different effects

A

ACh acting on M3 in smooth muscle causes contraction

ACh acting on M3 on endothelial cells causes relaxation

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5
Q

what are the features of second messenegrs that allow sensitivity and selectivity of a response

A

sensitivity -> signal amplification

selectivity -> temporal and spatial localisation

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6
Q

list some common secondary messengers

A

cAMP and cGMP
IP3, DAG
NO,CO
Ca2+

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7
Q

what effect does Gs activation have on adenylate cyclase action

A

increases its activity increasing cAMP production

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8
Q

what effect does Gi have on adenylyl cyclase

A

decreases its activity, decreasing the cAMP production

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9
Q

what effect does Gq/11 have on its secondary messenger?

A

increases IP3 and DAG production by phospholipase C

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10
Q

what enzyme produces IP3 and DAG, and from what substrate?

A

phospholipase C

PIP2 substrate

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11
Q

how do all 3 plasma membrane receptor types

GPCRs
LGICs
Tyrosine kinase linked receptors (intrinsic enzymes)

affect 2ndary messenger activity

A

GPCR G proteins alter the activity of enzymes and production levels of 2ndary messengers

LGICs alter ion entry (specifically Ca)

TKLRs phosphorylate and activate enzymes/protein kinases

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12
Q

describe phosphorylation process

A
  1. kinases target serine/threonine/tyrosine residues in proteins and phosphorylate them (adding phosphate group to their hydroxyl group)
  2. the phosphate group is negatively charged and so can cause conformational changed based on surrounding charges
  3. this can alter protein activity
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13
Q

what is signal amplification? define

A

taking a small starting signal eg 1x NT and making it a much bigger signal

‘activation of one receptor by one extracellular transmitter induces synthesis of multiple 2nd messengers and alters the activity of multiple targets’

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14
Q

how does signal amplification occur?

A
  1. increasing the no. of active molecules at each stage of a cascade
  2. using multiple pathways
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15
Q

Describe a signal amplification pathway and describe it

A
  • 1x NA acts on GPCR and activate 1 adenylate cyclase
  • 1x adenylate cyclase can make many cAMP molecules
  • 2x cAMP can activate a PKA
  • each activated PKA can phosphorylate many targets
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16
Q

what is BDNF? where is it synthesised and where does it end up

A

Brain Derived Neurotrophic factor

synthesised in primary sensory neurones and is transported to terminals

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17
Q

where does BDNF bind?

A

to trkB receptors on spinal/peripheral neurones and glia

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18
Q

what effect does BDNF have when it binds to trkB receptors

A

alters pain processing (sensitises pain pathways)

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19
Q

how does BDNF binding to trkB receptors alter pain processing?

A
  1. alters gene expression (eg increasing expression of Neuropeptides - NTs in dorsal horn)
  2. increases NMDA receptor acitvation and trafficking to cell surface (enhancing glutamate sensitivity)
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20
Q

describe trkB receptor activation

more in depth mechanism of intrinsic receptor activation

A
  1. at rest trkB receptors exist as poorly active monomers
  2. BDNF binding causes conformational change which allows dimerisation with another BDNF bound receptor
  3. autophosphorylation of eachother activates them, and allows phosphorylation of other tyrosine residues in the intracellular region of the dimer
  4. this phosphorylation causes another conformational change which allows the binding of other substrates
21
Q

describe the process of the assembly of the
trkB / GBR2 / SOS complex

GBR2 -> growth factor receptor bound protein 2 (an adapter protein)
SOS -> son of sevenless ( a guanine nucleotide exchange factor)

A
  1. GBR2 recognises the phosphorylated region of receptor and binds to it (preventing binding of other signalling molecules)
  2. SOS binds to GBR2
  3. SOS interacts with Ras (a small GTPase)
  4. this binding causes a conformational change in Ras which leads to dissociation of GDP - exposing guanine nucleotide binding site
  5. GTP binds to this activating Ras
  6. activated Ras dissociates from SOS and travels along the cell membrane triggering further downstream signalling
22
Q

describe Ras

A

small GTPase which is activated when bound to GTP

23
Q

what does GBR2 bind to

A

the phosphorylated region (binding site) on the trkB receptor dimer

it then binds to SOS

24
Q

what does SOS bind to

A

GBR2 and then Ras-GDP

25
Q

describe the process of the MAP kinase cascade

A
  1. activated Ras interacts with RAF activating it
  2. Activated Raf then phosphorylates MEK 🔊🔊🔊
  3. MEK then phosphorylates and activates MAPK 🔊🔊🔊
  4. Activated MAPK can phosphorylate many targets eg 🔊🔊🔊
    - cytosolic targets eg NMDA receptors
    - move into nucleus and activate several TFs (eg CREB)
26
Q

what terminates the MAP kinase cascade?

A

the hydrolysis of GTP by Ras to GDP

switches off the signal

27
Q

what is RAF?

A

a MEK kinase

28
Q

what is MEK?

A

a MAPK or ERK kinase

29
Q

what is MAPK

A

mitogen activated protein kinase

30
Q

what activates RAF

A

activated Ras

31
Q

what does RAF phosphorylate

32
Q

what does MEK phosphorylate

33
Q

what effect does activated MAPK have?

A

can phosphorylate NMDA receptors

can activate several transcription factors in nucleus eg CREB

34
Q

what could happen if the MAPK cascade isnt switched off and why?

A

the TFs it activates are involved in cell division so it could lead to tumour formation

35
Q

where does signal amplification occur in the within the MAPK cascade

A
  1. the GRB2-Sos complex can activate many Ras
  2. each Raf can phosphorylate many MEK
  3. each MEK can phosphorylate many MAPK
  4. MAPK can phosphorylate many targets

the phosphorylated trkB receptor can alternatively phosphorylate PLC
PLC activates PKC which phosphorylates and activates NMDA receptors increasing glutamate sensitivity

each occurs due to just 1 molecule of BDNF binding

36
Q

what G protein activates adenylyl cyclase

what G protein inhibits adenylyl cyclase

A

Gs activates

Gi inhibits

37
Q

what isoforms of adenylyl cyclase is activated by calcium / calmodulin

A

type 1, 3 and 8

38
Q

what isoforms of adenylyl cyclase is inhibited by calcium

A

types 5 and 6

39
Q

describe the process of PKA activation by cAMP

A

adenylate cyclase produces cAMP
cAMP binds to the regulatory subunit of PKA
the catalytic subunit can then dissociate from the regulatory subunit and phosphoryate targets

40
Q

what residues can PKA phosphorylate

A

serine and threone residues

41
Q

what are scaffolding proteins

A

proteins that bind enzymes to hold them in place, keeping their activity limited to certain regions of a cell
(spatial localisation)

42
Q

give an example of scaffolding protein

A

AKAP (A-Kinase Anchoring Proteins) are bound to the cell cytoskeleton. they also bind to cAMP to hold them in place and limit their activity to sub domains of the cell

they bind other signalling molecules to form anchored signalling pathways

43
Q

how can spatial localisation of signalling occur? 2 ways

A
  1. scaffolding proteins

2. based on nature of the molecule, eg DAG lipid soluble so remains in the membrane where it carrys out its activity

44
Q

what breaks down cAMP?

A

phosphodiesterase

45
Q

what can sustained [Ca} lead to

describe process of Ca2+ excitotoxicity

A

activates proteases, phospholipases and endonucleases which damage cytoskeleton, call membranes and DNA

can lead to cell death (excitotoxicity)

46
Q

what can cause elevated sustained Ca2+ levels

A
  1. increased glutamate and NMDA receptor activity (NMDA receptor is a ligand gated Ca channel)
  2. decreased Ca2+ buffering in cytoplasm
47
Q

in what ways can Ca act as a second messenger

A
  1. can cause NT release for example

2. can act via calmodulin to cause conformational changes in proteins activating/inactivating them

48
Q

how is low [Ca2+] maintained

A
  1. ATPases pumping into SR /ER / extracellular
  2. Na / K / Ca transporters
  3. opening of Cl- / K+ channels to hyperpolarise cell and prevent AP firing and further opening of Ca channels
  4. calcium buffering proteins

physiology and pharma (18 decks)

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