Lecture 4 Chemicals in the Brain Flashcards
what are the types of neurotransmitters
amino acids
monoamines
acetylcholine - fast
neuropeptides - slow
how are neurotransmitters stored and released
Synthesized locally in presynaptic terminal
Stored in synaptic vesicles
Released in response to local increase in Ca2
how are neuropeptides stored and released
Synthesized in the cell soma and transported to terminal
Stored in secretory granules
Released in response to global increase in Ca2+
how are fast neurotransmitters released
close to voltage gated ca2+ channels in terminal so released in short bursts when membrane depolarised
how are slow neurotransmitters released
stored in vesicles further from membrane so release slower as must migrate so released when ca2+ released sufficiently
what are amino acid transmitters
glutamate
GABA
Glycine
what are excitatory neurotransmitters
slightly depolarises the post synaptic cell’s membrane
glutamate (cns)
what are inhibitory neurotransmitters
slightly hyper polarises the post synaptic cell’s membranes
GABA (brain)
Glycine (spinal cord and brainstem)
what do diffuse modulatory systems do
Serotonin
Nt synthesised in small set of neurons, usually in brainstem and then acts across a large area
1 synthesising neuron can affect >100,000 neurons
what is the function of diffuse modulatory systems
mood sleep pain emotion appetite
why have multiple neurotransmitters
release of neurotransmitters (other than GABA or Glu) tends to activate or inhibit entire circuits of neurons that are involved in particular brain functions
how is glutamate made
synthesised in presynaptic terminal from 2 sources:
1) from glucose via the Krebs cycle
2) from glutamine converted by glutaminase into Glutamate
how is glutamate stored
loaded and stored in vesicles by vesicular glutamate transporters (VGLUTs)
how is glutamate recycled
reuptake by excitatory amino acid transporters (EAATs) in the plasma membrane of presynaptic cell and surrounding glia (convert Glu to glutamine and this is transported from the glia back to nerve terminals where it is converted back into Glu)
how is GABA made
synthesised from glu in a reaction catalysed by GAD
how is GABA stored
loaded and stored into vesicles by a
vesicular GABA transporter, GAT
(Gly uses the same transporter)
how is GABA recycled
cleared from synapse by reuptake using transporters on glia and neurons including non-GABAergic neurons
higher proportion of GABA is made de novo to refill vesicles rather than recycling to ensure enough as can be kept at Glu
what happens with too much Glu/too little GABA
hyper-excitability
epilepsy and excitotoxicity
eg cerebral ischaemia (electrochemical gradient abolished, Na+/K+ reversed, transporters release Glu in reverse, excitotoxic death (ca2+, enzymes, digestion)
what happens with too much GABA
sedation/coma eg GHB (date rape drug), GABA metabolite converted back to GABA
what are the types of monoamines
catecholamines and indolamines
examples of catecholamines
Dopamine
Epinephrine (adrenaline)
Norepinephrine
examples of indolamines
serotonin
how does dopamine synthesis occur
step 1 of catecholamine synthesis
tyrosine (TH) to dopa (Dopa DC) to dopamine (DA)
how can Parkinson’s be treated with dopamine
administration of
Levodopa (L-DOPA)
Dopa DC converts it to DA to inc amount
how is dopamine turned to epinephrine
catecholamine synthesis 2
DA (DBH) to NE (PNMT) to E
DBH located in synaptic vesicles only, and NE is the only transmitter synthesised within
vesicles
how are catecholamines stored
Loaded into vesicles by vesicular monoamine transporters (VMATs)
(proton gradient like Glu and GABA transporters)
how are catecholamines stored
Loaded into vesicles by vesicular monoamine transporters (VMATs)
(proton gradient like Glu and GABA transporters)
how are catecholamines stored
Loaded into vesicles by vesicular monoamine transporters (VMATs)
(proton gradient like Glu and GABA transporters)
how are catecholamines released
released by Ca2+ - dependant exocytosis
binds and activates receptor
how are catecholamines recycled
signal terminated by reuptake into the presynaptic axon terminal by transporters powered by electrochemical gradient (Dopamine transporters (DATs), Norepinephrine transporters (NETs))
what happens to catecholamines once back in cytoplasm
reloaded back into vesicles
enzymatically degraded by Monoamine oxidases (MAOs) or inactivated by Catechol-O-methyl-transferase (COMT)
how do amphetamines modulate catecholamine release and reuptake
reverses transporter, so pumps out transmitter and blocks reuptake (DA & NE)
how does cocaine and methylphenidate modulate catecholamine release and reuptake
(eg Ritalin) block DA reuptake into terminals
More DA in synaptic cleft – extended action on postsynaptic neuron
how does selegiline modulate catecholamine release and reuptake
MAO inhibitor (in dopaminergic nerve terminals) stop breakdown of DA, more released on subsequent activations (treatment of early-stagePD,depression anddementia), and overall increasing the available amount of DA
how does entacapone modulate catecholamine release and reuptake
COMT inhibitor (treatment of PD), increases the available amount of neurotransmitter
how is serotonin synthesised
tryptophan to 5-HTP to Serotonin aka 5-HT
how is serotonin stored
vesicles
how is serotonin recycled
signal terminated by reuptake (Serotonin transporters (SERTs)) on presynaptic membrane
destroyed by MAOs in the cytoplasm
how does fluoxetine affect serotonin release and reuptake
(eg Prozac) blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) (treatment of depression, OCD)
how does fenfluramine affect serotonin release and reuptake
stimulates the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity)
how does MDMA affect serotonin release and reuptake
causes NE and serotonin transporters to run backwards, releasing neurotransmitter into synapse/extracellular space (therapeutic potential in PTSD?)
how is Ach made
Choline acetyltransferase (ChAT, CAT) converts choline+Acetyl CoA (coenzyme A) into acetylcholine
how is Ach stored
packaged into vesicles by vesicular acetylcholine transporter (VAChT).
how is Ach broken down
rapidly degraded in synaptic cleft by acetylcholinesterase (AChE) Choline is transported back into the presynaptic terminal and converted to acetylcholine
how does AchE modulate Ach degradation
block the breakdown of ACh, prolonging its actions in the synaptic cleft
e.g. Neostigmine (treatment of myasthenia gravis, MG)
how are neuropeptides different from small molecule transmitters
Vary in their methods of synthesis and
release from small molecule transmitters
what are neuropeptides
Short polypeptide chains (3 to 36 amino acids)
Over one hundred neuropeptides described
e.g. endorphins, neuropeptide Y, substance P, endogenous opioids, vasopressin
how are small molecules transmitted
synthesised in cell body slow axonal enzyme transport synthesis and packaging of nt released, diffusion transport of precursors into terminal
how are small molecules transmitted
synthesised in cell body slow axonal enzyme transport synthesis and packaging of nt released, diffusion transport of precursors into terminal
how are peptides transmitted
synthesis of nt precursors and enzymes in cell body
transport down microtubule tracks
enzymes modify precursors to produce them
diffuse
degraded by proteolytic enzymes
how does neuropeptide degradation vary from small molecules
neuropeptide vesicle membrane recycled but not refilled
bind to and activate receptor
neuropeptides signalling is terminated by diffusion from site of release and degradation by proteases in the extracellular environment
how does neuropeptide release vary from small molecules
needs sustained or repeated depolarisation of Ca2+
release is slower than small molecule release and signals may be maintained for longer
what are other transmitters (retrograde signalling)
soluble gases - NO and CO
Endocannabinoids
how is NO made
NO made in postsynaptic neuron by NO synthase (activated by the binding of Ca2+ and calmodulin)
how is NO stored
not stored but rapidly diffuses from its site of synthesis. Diffuses between cells (into presynaptic cell - retrograde transmitter)
what does NO do
Activates guanylyl cyclase which makes the second messenger cGMP
how is NO eliminated
in a few secs of being produced NO is converted to biologically inactive compound
what is NO used for
Potentially useful for coordinating activities of multiple cells in a small region (tens of micrometers)
what are Endocannabinoids
Small lipids which mostly cause reduced GABA release at certain inhibitory terminals (lower inhibition)
cannabinoid active component in marijuana
