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

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

presynaptic sites of BDNF/TrkB

Answer 19

regulation of release

Question 20

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 - tonic inhibition, ambient extracellular GABA binds to extrasynaptic GABAaRs and modulates resting membrane potentials and cell excitability - phasic inhibition, GABA is released from presynaptic terminals and binds to postsynaptic GABAaRs

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

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