lecture 13: postsynaptic mechanisms

Question 1

what is the neurotransmitter response controlled by

Answer 1

available receptors

Question 2

what does the action of a neurotransmitter depend on

Answer 2

its receptors and their location

Question 3

receptors may be:

Answer 3

• postsynaptic
• presynaptic
• extra synaptic
• excitatory or inhibitory
• fast or slow

A single neurotransmitter may have multiple actions through multiple different receptors subtypes located on different cell types

Question 4

G-protein coupled receptors

Answer 4

• surface membrane receptors
• respond to a multitude of signals
• target of a multitude of drugs
• metabotropic

Question 5

metabotropic def

Answer 5

= accessing metabolic enzymes within the cell, not forming ion channels (not changing influx of calcium/sodium directly) –> changing it by accessing metabolic enzymes and then going to change the receptor

Question 6

examples of GPCR ligands that can activate GPCR

Answer 6

GPCR have a variety of ligands including:
1. Neurotransmitters
- Glutamate
Metabotropic GLuRs (mGluRs)
- Acetylcholine
muscarinic AchR (mAchRs)
- dopamine
D1-like, D2-like
2. Hormones
3. Sensory signals
- light
- odours
- taste
4. and many others

Question 7

how do GPCRs work

Answer 7

• slow acting receptors
• metabotropic receptors
• 7 transmembrane domains (passes through the membrane 7 times)
• ligand binds to cup on the surface which causes conformational changed which activates the G proteins
• act as dimers

Question 8

what is the ligand-receptor interaction mediated by

Answer 8

• G proteins (not forming an ion channel just forming a functional unit)
• trimeric GTP-binding proteins
• dissociate into two components upon activation
  –> Ga and B/Y

Question 9

G-protein activation leads to..

Answer 9

1. activation of membrane bound enzymes
   - adenyl cylclases
   - phosphodiesterases
   - phosholipases
2. regulation of second messengers
   - Generates cAMP
   –> important for plasticity phase
   –> activate protein kinase A (PKA)
   - Hydrolysis of cAMP
   –> reduce levels of cAMP
   –> negative regulation (PKA)
   - Hydrolysis of membrane phospholipids, generation of DAG and IP3
   –> release of Ca2+ from internal stores

Question 10

Dopamine receptors

Answer 10

1. D1-like receptors (D1 and D5)
   - stimulation of adenylate cyclase
   - coupled to Gs
   - mediate excitatory neurotransmission
2. D2-like receptors (D2, D2, and D4)
   - Inhibition of adenylate cyclase
   - coupled to Gi/Go
   - mediate inhibitory neurotransmission

Question 11

characteristics of enzyme linked receptors

Answer 11

• cytosolic domain with intrinsic activity
  or
• direct association with an enzyme
• each subunit of an enzyme-linked receptor has only one transmembrane domain = single pass protein

Question 12

where are TrKB found

Answer 12

glia, neuronal cell bodies, presynaptic terminals, and on dendrites

Question 13

what is TrkB

Answer 13

= tropomyosin receptor kinase B
- a receptor tyrosine kinase

Question 14

Brain derived neurotropic factor (BDNF)

Answer 14

• is a neurotrophin, neuropeptide & neuromodulator
• packaged into LDCV
• which binds to TrkB receptors
• has lots of different effects

Question 15

how can we control our BDNF levels

Answer 15

1. Exercise
   - increase BDNF at any age
2. sleep
   - missed sleep = less BDNF = ability to form connections lowers
3. nutrition
   - fat + sugar = less BDNF = lower cognition
4. stress
   - cortisol acts against BDNF = ability to form new memories are diminished

Question 16

formation of BDNF

Answer 16

• synthesized as the precursor pre- proBDNF
• which is processed to:
  –> proBDNF is a signalling protein in its own right
  –> associated with apoptosis and LTD.
  and
  –> matureBDNF (mBDNF)
  –> is a signalling molecule
  –> associated with cell survival and LTP

this final product is what has the positive impact on cells
- proBDNF = negative, keeps plasticity at bay
- matureBDNF = activates synapses and strengthens connections within the brain

Question 17

are enzyme linked receptors slow or fast

Answer 17

slow acting receptors

Question 18

what do the BDNF/TrkB act on

Answer 18

• second messenger pathways
• ligand gated ion channels (indirectly)
• voltage gated ion channels (indirectly)
• local protein synthesis
• gene expression

–> and can therefore have delayed and long lasting impacts on neurons

Question 19

what happens at presynaptic sites of BDNF/TrkB

Answer 19

regulation of release

Question 20

what happens at postsynaptic sites of BDNF/TrkB

Answer 20

“local protein synthesis” and gene expression

Question 21

GABA receptors overview

Answer 21

GABA = gamma aminobutryic acid
- response depends on type of receptors available
GABA-A receptors = ionotropic
GABA-B receptors = metabotropic

Question 22

GABA synthesis

Answer 22

• GABA is an amino acid but it is not found in proteins
• GABA is synthesised in GABA’ergic neurons by glutamic acid decarboxylase (GADs)
• GADs therefore are good markers for GABA’ergic neurons

Question 23

what does the function of GABA depend on

Answer 23

• what type of recptors are present on the membrane

Question 24

where are GABAa receptors found

Answer 24

Widespread = CNS and PNS eg:
- limbic system
- eye
- amygdala
- neurons, oligodendrocytes and schwann cells
- neuromuscular junction

Question 25

GABAa receptors structure

Answer 25

multiple possible subunits form pentameric chloride ion channels

Question 26

GABAa receptors role in inhibitory postsynaptic potential (IPSP)

Answer 26

- activation of GABA (or glycine)-gated ion channels causes an IPSP - via opening of chloride ion channels and resulting influx of Cl- - at synaptic and extrasynaptic sites - results in inhibition of the target cells --> more negative inside, and thus less likely to fire - causes tonic and phasic inhibition

Question 27

IPSP def

Answer 27

= inhibitory postsynaptic potential - a transient hyperploarization of the postsynaptic membrane potential caused by the presynaptic release

Question 28

GABAa receptors and anxiety

Answer 28

- people with anxiety disorders can have reduced GABA activity - drugs that enhance GABA action are anxiolytic = reduce anxiety (or panic) - lower GABAR = reduced inhibition = lost the ability to calm the system down

Question 29

Acetylcholine receptors location

Answer 29

--> widespread location - neuromuscular junction - autonomic ganglia - postganglionic parasympathetic synapses - interneurons in striatum and cortex - midbrain - cortex, hippocampus and amygdal

Question 30

what responses do ACh cause

Answer 30

same signal = different responses - the specific way a cell responds to an extracellular signal depends on its receptors and intracellular machinery used to interpret the signal Heart muscle = decreased rate and force of contraction Salivary gland = secretion GPCR = G-protein coupled receptor/metabotropic receptors Skeletal muscle = contraction Ionotropic receptors = ligand gated ion channels

Question 31

muscarinic AchR: metabotropic

Answer 31

- sensitive to muscarine (mAChR) - g-PROTEIN COUPLED (gpcr) - 'metabotropic' found for example in: - glia - heart muscle - salivary glands

Question 32

nicotinic AchR: ionotropic

Answer 32

- sensitive to nicotine (nAChR) - ligand gated ion channel - mediate fast synaptic transmission - occur in high density at neuromuscular junction - 20,000 um^2 - also sensitive to a-bungarotoxin

Question 33

synthesis and degradation of ACh

Answer 33

- choline taken up into nerve terminal -ACh synthesized by choline acetyltransferase - ACh transported into vesicles - following synaptic release ACh degraded by acetylcholinesterase --> acetylcholine esterase inhibitors are used as one of the only therapies for alzeimers disease

Question 34

acetylcholine receptors: ionotropic: nAChR process

Answer 34

Signal- acetylcholine released - from axons diffuses - through extracellular matrix binds - acetylcholine receptors on postsynaptic cell results - in depolarisation of muscle cell (Na+ and K+); opening of voltage gated sodium channels; action potential and muscle contraction

Question 35

tonic inhibition

Answer 35

ambient extracellular GABA binds to extrasynaptic GABAaRs and modulates resting membrane potentials and cell excitability

Question 36

phasic inhibition

Answer 36

GABA is released from presynaptic terminals and binds to postsynaptic GABAaRs