Chemicals in the brain Flashcards
How are the pool of vesicles anchored to the cytoskeleton?
Synapsin
What does calcium activate?
Calcium calmodulin activated kinase 2
What does CCK2 do?
Phosphorylates synapsin so it no longer binds to cytoskeleton
Where is the snare complex found?
Active zone
What happens after the vesicle docks?
Snare complex pull membranes together
Ca2+ binds to synaptotagmin
Catalyzes fusion of membrane by binding to membranes and proteins
Describe vesicle recycling
Vesicle membrane is rapidly recovered via ENDOCYTOSIS, new vesicles bud off and are refilled with transmitter
What does the botulinum toxin do?
Decreases neuromuscular transmission ACh
acts directly at the neuromuscular junction. The muscles lose all input and so become permanently relaxed (treatment of muscle spasms).
What does the tetanus toxin do?
Decreases interneurons at spinal cord, GABA, Gly
inhibits the release of Glycine and GABA at inhibitory neurons, resulting in dis-inhibition of cholinergic neurons, which causes permanent muscle contraction.
What are vesicular transporters powered by?
Proton gradient
ATPase proton pump loads up vesicles with H+
making vesicles acidic (pH5.5) compared to neutral pH of cytoplasm (pH7.2)
e.g. 1 glutamate traded for 1 H+ (counter-transport mechanism)
What are the plasma membrane transporters powered by?
Electrochemical gradient
[Na+] higher outside / [K+] higher inside
Glutamate co-transported with 2 Na+
What are the 4 categories of neurotransmitters?
Amino acids
Monoamines
Acetylcholine
Neuropeptides
What do amino acid, monoamine and acetylcholine transmitters have in common?
Synthesized locally in presynaptic terminal
Stored in synaptic vesicles
Released in response to local increase in Ca2+
Where are neuropeptides synthesised?
cell soma and transported to the terminal
Where are neuropeptides stored?
Secretory granules
How are neuropeptides released?
Released in response to global increase in Ca2+
Give example of fast neurotransmitter
Amino acids
Give example of slow neurotransmitter
Neuropeptide
What is meant by excitatory?
slightly depolarises the postsynaptic cell’s membrane
Give an example of an excitatory neurotransmitter
Glutamate
What is meant by inhibitory?
slightly hyperpolarises the postsynaptic cell’s membrane
Give an example of an inhibitory neurotransmitter in the brain
(γ-aminobutyric acid) GABA
Give an example of an inhibitory neurotransmitter in the spinal cord and brain stem
Glycine (Gly)
What do diffuse modulatory systems function in?
mood sleep pain emotion appetite
What is a common principle of the diffuse modulatory system?
Synthesised by small set of neurons mostly arising from the brainstem but gives off many connections
Why have more neurotransmitters?
Further control- regulates balance of excitation and inhibition
Neurotransmitters and neuromodulation
Give the two sources glutamate is released from
From glucose via the Krebs cycle
From glutamine converted by glutaminase into Glutamate
How is glutamate loaded and stored in the vesicle?
loaded and stored in vesicles by vesicular glutamate transporters (VGLUTs)
How does reuptake of glutamate occur?
Reuptake by excitatory amino acid transporters (EAATs) in the plasma membrane of presynaptic cell and surrounding glia
What happens to glutamate by the glial cells?
glial cells convert Glu to glutamine and this is transported from the glia (“ball boys”) back to nerve terminals where it is converted back into Glutamate.
How is GABA synthesised?
synthesized from glutamate (Glu) in a reaction catalyzed by glutamic acid decarboxylase (GAD)
How is GABA loaded and stored in vesicles?
loaded and stored into vesicles by a vesicular GABA transporter, GAT (Gly uses the same transporter)
How does reuptake of GABA occur?
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
What does too much Glu and too little GABA lead to?
hyper-excitability – epilepsy
excitotoxicity
What does too much GABA lead to?
Sedation/Coma
What is cerebral ischemia?
the metabolic events that retain the electrochemical gradient are abolished
reversal of the Na+ / K+ gradient
transporters release glutamate from cells by reverse operation
excitotoxic cell death (Ca2+ -> enzymes -> digestion)
What is GHB?
a GABA metabolite that can be converted back to GABA
Increases amount of available GABA
too much leads to unconsciousness and coma
What are the 2 families of monoamines?
Catecholamines
Indolamines
What are the catecholamines?
Dopamine
Epinephrine/adrenaline
Norepinephrine
What are the indolamines?
Serotonin
How is dopamine synthesised?
Tyrosine- Ldopa- Dopamine
What drug is given in parkinson’s disease?
Levodopa
How is norepinephrine synthesised?
From dopamine by DBH
Why is norepinephrine stored and made in vesicles?
DBH is only present in the vesicles
How is epinephrine made?
From norepinephrine
In the cytoplasm, what happens to catecholamines?
- reloaded back into vesicles
- enzymatically degraded by Monoamine oxidases (MAOs)
or - inactivated by Catechol-O-methyl-transferase (COMT)
What does amphetamine do?
reverses transporter so pumps out transmitter and blocks
reuptake (DA & NE)
What does cocaine and methylphenidate do?
block DA reuptake into terminals. More DA in synaptic cleft – extended action on postsynaptic neuron
What does selegiline do?
MAO inhibitor found in dopaminergic nerve terminals thus preventing the degradation of DA allowing more to be released on subsequent activations (treatment of early-stagePD,depression anddementia).
What does Entacapone do?
COMT inhibitor (treatment of PD)
How is serotonin synthesised?
Tryptophan- 5htp - 5ht
What does fluoxetine do?
blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) (treatment of depression, OCD)
What does fenfluramine do?
stimulates the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity)
What does MDMA do?
methylenedioxymethamphetamine (ecstasy) causes NE and serotonin transporters to run backwards releasing neurotransmitter into synapse/extracellular space (assessed for therapeutic potential in PTSD)
How is ACh degraded?
rapidly degraded in synaptic cleft by acetylcholinesterase (AChE)
What are AChE inhibitors?
AChE (Acetylcholinesterase) inhibitors
block the breakdown of ACh, prolonging its actions in the synaptic cleft e.g. Neostigmine (treatment of myasthenia gravis, MG)
Describe neuropeptides
slow transmission
Vary in their methods of synthesis and
release from small molecule transmitters
Short polypeptide chains (3 to 36 amino acids)
Over one hundred neuropeptides described
e.g. endorphins, neuropeptide Y, substance P, endogenous opioids, vasopressin
Describe neuropeptide release and degredation
Follow the secretory pathway and NOT released in the same manner as small molecule transmitters
dense core vesicle fusion and exocytosis occurs as a result of global elevations of Ca2+ (sustained or repeated depolarization or release of Ca2+ from intracellular stores)
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
release is slower than small molecule release and signals may be maintained for longer
What does nitrogen oxide do?
Nitric oxide made in postsynaptic neuron by Nitric oxide synthase
(activated by the binding of Ca2+ and calmodulin)
2) The gas is not stored but rapidly diffuses from its site of synthesis. Diffuses between cells (into presynaptic cell - retrograde transmitter)
Activates guanylyl cyclase which makes the second messenger cGMP
4) Within a few seconds of being produced NO is converted to biologically inactive compound (switching off the signal)
5) 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.
A cannabinoid is also the active component of marijuana (Cannabis sativa).
