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BMSc - Synaptic Plasticity and Cognition > Insulin > Flashcards

Insulin Flashcards

1
Q

What is the main action of insulin?

A

Enhances uptake, utilisation and storage of glucose

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2
Q

Describe an insulin receptor (IR)

A

Its one large transmembrane glycoprotein complex

With two alpha and two beta subunits linked by disulphide bridges

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3
Q

Describe the alpha subunit in the insulin receptor (IR)

A

Extracellular

Insulin binding domain

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4
Q

Describe the beta subunit in the insulin receptor (IR)

A

Transmembrane proteins with intrinsic tyrosine kinase activity

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5
Q

Which methods can be used to determine IR expression in CNS?

A

Immunocytochemistry
In situ hybridisation
Western blots & PCR

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6
Q

Outline in situ hybridisation

A

Labelled anti-sense oligonucleotide probes inserted which are specific to IR subunits
Detects mRNA

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7
Q

How does peripheral insulin get into the brain?

A

Active transport across the BBB via a regulated, saturable insulin transporter

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8
Q

How may insulin be released locally from the CNS?

A

Depolarisation of insulin mRNA expressing neurons should cause insulin relase

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9
Q

What is the main role of insulin in the CNS?

A

Mediate cerebral glucose uptake in glial cells

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10
Q

Hyper-insulinaemia is a risk factor for Parkinson’s disease

True/False

A

False

risk factor for dementia

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11
Q

How does insulin administration affect memory formation?

A

Improves it

Craft et al 1999

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12
Q

Why doe we think that insulin is relevant to learning and memory?

A

IRs concentrated in brain regions involved in learning and memory
Hippocampus and amygdala

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13
Q

How does insulin affect synaptic strength?

A

Increases synaptic strength of excitatory synapses

Man et al 2000

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14
Q

What is streptozotocin?

A

A diabetic inducing agent

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15
Q

What effect does streptozotocin have on memory?

A

Memory impairment

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16
Q

Which NMDAR features does insulin enhance?

A

NMDAR single channel currents

NMDAR mediated synaptic transmission

17
Q

Which isoforms of NMDAR does insulin enhance?

A

NR1-NR2A and NR1-NR2B

These are prominent in the hippocampus!

18
Q

Outline insulin receptor signal transduction

A

Binds to alpha subunit
Causes autophosphorylation of beta subunits
Stimulates intrinsic tyrosine kinase activity
Phosphorylation then triggers the activation of other signalling cascades

19
Q

Phosphorylation of IR causes activation of which signalling cascades?

A

IRS proteins and Src proteins (PI3K)

Shc protein

20
Q

What does Shc protein do?

A

Mediates association of IR with Grb-2-SOS complex

Activates Ras-Raf-MAPK

21
Q

Which inhibitors block insulin action?

A

IR tyrosine kinase inhibitors eg tyrphostin (Skeberdis 2001)
PKC inhibitors (Liao 1999)
Src TK inhibitors (Liao and Leonard 1999)

22
Q

How does insulin effect NMDAR surface expression?

A

Increases exocytosis

Inhibits endocytosis

23
Q

How does insulin increase NMDAR expression and how do we know?

A

Via SNAP-25 dependent exocytosis

Botox injections cleave SNAP-25 and prevents this exocytosis
With botox there is reduced NDMAR current
Skeberdis 2001

24
Q

How does SNAP-25 driven insulin receptor exocytosis work?

A 
IR activated
Activates IRS proteins
Activates PI3K
Then activates abnormal protein kinase C
This increases SNAP-25 activity which then causes the receptors exocytosis
25
Q

Through which signalling pathways does insulin increase NMDA responses?

A

PI3K and MAPK

Because application of inhibitors of these stop the increase in current

26
Q

How may insulin modulate LTD?

A

Depressing AMPAR mediated EPSCs in hippocampal neurons by reducing surface AMPAR expression

Man et all 2000

27
Q

Low concentrations of insulin induce LTP

True/false

A

False
Low conc produces transient synaptic depression
High conc induces LTD

28
Q

Insulin decreases NMDAR EPSCs

T/F

A

F

Depresses AMPAR EPSCs but not NMDARs

29
Q

Which AMPAR subunit does insulin supress?

A

GluA2

But not GluA1

30
Q

How do we know insulin affects AMPAR subunits?

A

Immunocytochemistry shows less of them

Man et all 2000

31
Q

How does hypertonic sucrose affect insulin mediated subunit endocytosis?

A

Inhibits clathrin coating the vesicle which means it cant endocytose

32
Q

What can be given to block insulin-mediated endocytosis of AMPAR?

A

Hypertonic sucrose

Post-synaptic dialysis with Anti-IR Abs

33
Q

Why do we think insulin and memory are linked?

A

In rodents, MWM training upregulated IR mRNA and protein in CA1 region
Increase in IR staining also observed

Zhao et al 1999

34
Q

What biochemical changes were observed following training in the MWM?

A

Increased tyrosine phosphorylation in 52 and 66 kDa proteins
Increase in Shc-66
Accumulation of Grb (52kDa)
Increase in active MAPK

Zhao et al 1999

35
Q

Which neurodegenerative disorder is insulin linked to?

A

AD

36
Q

How may insulin be useful in AD treatment?

A

Prevents Ab derived diffusible ligands (ADDL) induced synapse loss

37
Q

Which signalling pathway does insulin enhance NMDA via?

A

PI3K-MAPK

when this is blocked u dont get insulin mediated increase in NMDARs

38
Q

What is insulin induced LTD dependent on?

A

Postsynaptic IR activation

BMSc - Synaptic Plasticity and Cognition (5 decks)

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