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CNS > Neurochemistry 2 > Flashcards

Neurochemistry 2 Flashcards

1
Q

Where does the synthesis of ACh take place

A

In cytosol of nerve terminal

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2
Q

Where is choline acetyltransferase only found

A

In the nerve terminals of cholinergic neurons

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3
Q

Overview of synthesis of ACh

A
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4
Q

How id Acetyl CoA formed

Where is it generated

A

Oxidative decarboxylation of pyruvate

Generated in mitochondria but also in the cytosol by LCFAs and certain AAs that are present everywhere

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5
Q

Where is there a high conc of choline

Where is there a high uptake system for choline

A

High conc in blood system

Most cells have an uptake system for choline but only cholinergic systems have this high uptake system

they can concentrate a lot of choline into the nerve terminals

once it is synthesised it goes to the vesicles

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6
Q

What 2 receptor types can ACh bind to

A

IONOTROPIC - nicotinic

METABOTROPIC - muscarinic

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7
Q

What is the structure of the nicotinic ACh receptor channel

What are its subunits

A
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8
Q

How does the nAChR complex bind ACh

A

each complex has 2 binding sites for ACh

Mostly on alpha subunits, though partial involvement of δ and γ subunits

Ligand binding opens channel and allows influx of Na+

Alpha chains that line the transmembrane region have large amounts of negatively charged AAs, making the pores of the channel -vely charged and it will attract +vely charged ions

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9
Q

Define antagonist

A

Compound which binds to the receptor

Lacks intrinsic activity

Instead it blocks the activity of the physiological ligand

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10
Q

Agonists that bind to the nAChR, including the endogenous agonist

A

ACh = endogenous agonist

Nicotine = an agonist of ACh ionotropic receptor - a plant alkaloid

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11
Q

Antagonist of nAChR

A

α-bungarotoxin

An antagonist of ACh ionotropic receptor

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12
Q

What do M1, M3 and M5 mAChRs activate

A

Phospholipase C (PLC) via G0 or Gq

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13
Q

MOA of M2 and M4 mAChRs

A

Inhibit adenylate cyclase via Gi

Stimulate a K+ channel via Gs

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14
Q

Where are mAChRs present

Functions

A

In striatum and in peripheral nervous system

Also mediate autonomic functions acting on the heart, SM and exocrine glands

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15
Q

Agonists that bind to mAChRs

A

Muscarine - fungal alkaloid that binds with high affinity

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16
Q

Antagonists that bind to mAChRs

A

+ => inhibited by

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17
Q

Summary of ligands for ACh receptors

A
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18
Q

Activators of nicotinic receptors

A

ACh

Nicotine

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19
Q

Inhibitors of nicotinic receptors

A

a-bungarotoxin

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20
Q

substances that do not bind to nicotinic receptors

A

Muscarine

Atropine

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21
Q

Activators of muscarinic receptors

A

ACh

Muscarine

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22
Q

Inhibitors of ACh receptors

A

Atropine

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23
Q

Substances that do not bind to muscarinic receptors

A

Nicotine

a-bungarotoxin

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24
Q

How is ACh inactivated

How is Choline taken back up

A

ENZYMATIC DEGRADATION

Degraded by acetylcholinesterase in synaptic cleft where ACh is at high conc

Catalytic rate of enzyme = 104-105 mols/s

one of the most rapid enzymes known - why ACh is used at NMJs so that we have good control over muscles

Choline is taken back up into the nerve terminal by high affinity Na+ dependent uptake system

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25
Q

Inhibitors of acetylcholinesterase

Sarin nerve gas - lethal dose = 0.5mg

Neostigmine

A
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26
Q

Localisation of AChesterase

A
27
Q

MOA of myasthenia gravis (autoimmune disorder causing muscle weakness)

A

Patients sera contain antibodies directed against their own nAChRs

results in a decreased number of functional AChRs on muscle cells

Defective NM transmission leading to muscle weakness

28
Q

Neostigmine as an inhibitor of ACh

A
29
Q

What are the excitatory AAs (EAAs)

A

Glutamate

Aspartate

Homocysteic acid (sulfur containing)

Produce an EXCITATORY response in neurons - neuron is more likely to send an AP

30
Q

What is the most important NT for normal brain function

A

Glutamate

Nearly all excitatory neurons in CNS are glutamatergic

glutamate is present in all cells

31
Q

Synthesis of glutamate

What happens to glutamate once it has been released

A

Glutamate is synthesised from glutamine by glutaminase

Glutamate that has been released is taken up by astrocytes

Here it is converted back to glutamine by glutamine synthetase

32
Q

Ionotropic receptors and their subtypes

A

Glutamate binds to all

33
Q

Metabotropic Glu EAA receptors and their subtypes

A
34
Q

Consequence of switching from NR2B to NR2A (NMDA ionotropic glu EAA receptor subtype)

What is it regulated by

A

Learning capability is diminished

NMDA and AMPA receptors are key receptors in the formations of memories

Glu R1 and Glu R2 used when we’re learning something, but when its consolidated it switches to Glu R2 and Glu R3

35
Q

For the receptor AMPA,

  1. Ions flux through open channel
  2. Opening of channel is triggered by
A
  1. Influx of Na+ only
  2. Glu binding
36
Q

For the receptor Kainate,

  1. Ions flux through open channel
  2. Opening of channel is triggered by
A
  1. Influx of Na+ only
  2. Glu binding
37
Q

For the receptor NMDA,

  1. Ions flux through open channel
  2. Opening of channel is triggered by
A
  1. Influx of Na+ and Ca2+
  2. Glu binding + mebrane depolarisation
38
Q

What are the subunits of ionotropic Glu (or EAA) receptors derived from

A

A different ancestral gene than AChR

39
Q

Name the NMDA receptor antagonists

What is their MOA

A

D-AP5

MK801

40
Q

How are NMDA receptors different from others

A

EC portion of the receptor is much larger than it is for the nicotinic ACh receptor

41
Q

Role of glycine with the NMDA receptor

A

Regulates its activity by keeping the channel open for longer

42
Q

When is Mg2+ found in an NMDA receptor

A

in the CLOSED state

blocks the flow of Na+ and Ca2+ into the cell and it has to be removed before Ca2+ and Na+ can be allowed in

43
Q

How do AMPA and NMDA receptors (found in close proximity in the same post synaptic membrane) act together

A

AMPA receptor opens quickly upon Glu binding (< 1 ms)

NMDA receptor opens slowly (> 2ms)

Ligand gated => Glu must bind

Voltage dependent => there must be entry of Na+ to change the transmembrane potential

This removes the Mg2+ block from the channel

44
Q

Structure of metabotropic Glu receptors

how are the different groups different

A

7 membrane spanning peptide

at least 8 sutypes, mGluR1-8, have been cloned

3 CLASSES

Group 1 - mainly postsynaptic

Group 2 and 3 - mainly presynaptic (glutamate can act on the neuron that released it)

45
Q

Describe Group I metabotropic Glu receptors

A

Mainly POSTSYNAPTIC

46
Q

Describe Group II and III metabotropic Glu receptors

A

Mainly PRESYNAPTIC

Glu can act on the neuron that released it

47
Q

Different classes of metabotropic receptors

A
48
Q

What important function do metabotropic Glu receptors play a role in

A

Memory function

mGluR inhibitors block memory formation at some synapses (especially grp 1 as they can potentiate the NMDA receptor opening)

NMDA receptor activation potentiates signalling via mGluRs

49
Q

MOA of excitatory AA receptors and neuronal cell death in stroke

A

ISCHAEMIA

Block in blood supply

Excessive Glu release causes over-stimulation of NMDA receptors - excess Ca2+ influx into post synaptic neurons

Leads to excitotoxic cell death

50
Q

Effect of Ca2+ on excitotoxicity

A

Large influx of Ca2+

  • Can activate calpains, phospholipases, NOs (ox damage), nucleases etc that can lead to very rapid cell death by necrosis
  • Ca2+ is sequestered into mito. resulting in swelling and rupture of mito. - delayed cell death (window for treatment)
  • NMDA-R antagonists D-AP5 and MK801 provide protection in models of ischaemia
51
Q

What substances provide protection in models of ischaemia

A

NMDA-R antagonists D-AP5 and MK801

52
Q

Name the inhibitory AA NTs

A

GABA

Glycine

53
Q

MOA of inhibitory NT receptors

A

Influx of -vely charged ions - Cl-

Inside of cell becomes MORE -ve

HYPERPOLARISATION of post-synaptic cell making it less likely to initiate an AP

54
Q

MOA of excitatory NT receptors

(NMDA, AMPA, nicotinic AChR)

A

Influx of +vely charge ions - Na+

Inside of the cell becomes LESS -ve

Depolarisation of post-synaptic cell makes it more likely to initate an AP

55
Q

What proportion of synapses uses GABA

How is it synthesised

presence of what substance indicates a GABAergic neuron

A

33% of synapses in brain use GABA - main inhibitory NT in the brain

Synthesised from glutamate // glutamic acid decarboxylase

Presence of GAD indicates a GABAergic neuron

56
Q

Name the main NT in the spinal cord

A

Glycine

57
Q

How is GABA deactivated

A

By being taken up into nearby glial cells

also taken up by presynaptic neuron and recycled into synaptic vesicles

58
Q

Ionotropic GABA receptors

A

GABAA

GABAC

59
Q

Metabotropic GABA receptors

A

GABAB

60
Q

What is the GABAA receptor structurally related to

What is the ion channel selective for

How is it inactivated

A

Structurally related to nAChR

Ion channel is selective for Cl- ions

Inactivated - GABA is removed from synaptic cleft by transporters

61
Q

How does Valium (diazepam) act

A

Through modulating GABA-A receptor signalling

Cl- enters the cell => hyperpolarisation

Benzodiazepines (e.g. diazepam) and barbituates enhance the hyperpolarising effect of GABA

62
Q

What compounds enhance the hyperpolarising effects of GABA

A

Benzodiazepines (eg diazepam) and barbituates

63
Q

MOA of presynaptic inhibition

A

Inhibitory NT binds to receptors on the presynaptic cell

Reduction in depolarisation of the presynaptic nerve terminal

Less Ca2+ influx

Less excitatory NT release

64
Q

Overview of NT receptor classification

A

CNS (36 decks)

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