Lecture 4 Flashcards
What is a catechol group?
Phenol ring with -OH groups in 3 and 4 positions.
What are catecholamines synthesised from in the body?
Tyrosine.
What 4 major transmitters are catecholamines?
Adrenaline, Noradrenaline, Dopamine, Serotonin.
Why is Tyr transported into the brain from the blood?
Because the brain lacks phenylalanine hydroxylase (enzyme that converts Phe to Tyr).
Which transmitter is associated with motor function and lost in Parkinson’s disease?
Dopamine.
Catabolism of catecholamines is performed by which 2 enzymes?
Monoamine oxidase (MAO), Catechol 0-methyltransferase (COMT).
How is Dopamine synthesised from Tyrosine?
Tyrosine reacted with enzyme Tyrosine β-hydroxylase, forming L-Dopa.
Dopa reacted with enzyme Dopa decarboxylase forming Dopamine.
How is Noradrenaline synthesised from Dopamine?
Dopamine reacted with enzyme β-hydroxylase forming Noradrenaline.
How is Adrenaline formed from Noradrenaline?
Noradrenaline reacted with enzyme Phenylethanolamine N-methyl transferase (PNMT), forming Adrenaline.
Who was Parkinson’s first described by and when?
James Parkinson. 1817.
Mean age of onset of Parkinson’s?
~60 years.
How many over 65s does Parkinson’s affect?
1-2%.
Three main symptoms of Parkinson’s?
Muscle rigidity, tremor, bradykinesia.
Parkinson’s is a multifactorial disease. Name 3.
Age.
Environmental factors.
Genetics.
What happens neurologically in Parkinson’s?
Degeneration of pigmented cells of the ‘substantia nigra pars compacta’ in basal ganglia.
What does Parkinson’s result in neurologically?
> 50% depletion of Dopamine.
What catecholamine is administered to treat Parkinson’s disease, and what is it converted into?
L-DOPA.
Transported to brain and converted to dopamine.
Why is a Dopa decarboxylase inhibitor simultaneously administered alongside the L-DOPA when treating Parkinson’s?
Because this inhibitor can’t penetrate into the brain, and so prevents the rest of the body metabolising the L-DOPA into Dopamine, which can’t cross the blood-brain barrier.
What inhibitors can also be administered to reduce Dopamine degradation?
Inhibitors of MAO and COMT.
What is serotonin (5-HT) synthesised from, and via which enzymes?
Synthesised from tryptophan, using tryptophan hydroxylase and 5-hydroxytryptophan (5-HTP) decarboxylase.
How many different types of 5-HT receptors are there?
14.
What class of drugs can act as 5-HT agonists, mimicking serotonin at 5-HT2A receptors?
Hallucinogenic drugs, e.g. LSD.
How is serotonin action terminated?
Mainly by re-uptake from synapse via 5-HT re-uptake transporter on presynaptic neurone.
By what enzyme can 5-HT be catabolised (therefore inactivated)?
MAO.
What is the intermediate product between L-Tryptophan and Serotonin?
5-Hydroxy-L-Tryptophan (5-HTP)
In what system are amino acids found at the highest concentration in the body? What concentration is this?
CNS.
30mM.
What type of amino acids are found in the CNS? And what are they made from?
Non-essential amino acids.
Made in situ from glycolytic and citric acid intermediates.
What are the 4 amino acids found in the brain?
Glu, Asp, Gly, GABA.
Which amino acids in the brain are excitatory?
Dicarboxylic amino acids (glutamate, aspartate).
Which amino acids in the brain are inhibitory?
Monocarboxylic amino acids (Glycine and GABA)
Which 2 amino acids are MAJOR transmitters in the brain?
Glycine and GABA.
How many known examples of small peptide transmitters are there?
Around 100.
Where are small peptide transmitters the most common?
Hypothalamus.
As what are peptide transmitters first synthesised, where are they transported, and how are they activated?
Synthesised as large precursor proteins,
Transported to synaptic release site,
Activated by proteolytic cleavage.
Are peptide transmitters fast or slow?Do peptide transmitters exhibit fast or slow postsynaptic effects?
Slow.
What molecules terminate peptide transmitters?
Extracellular proteases.
Peptide transmitters are often co-released, but with what?
Other classical transmitters.
Opioids are one type of peptide transmitter. Three types of endorphins?
Endorphins, Enkephalins, Dynorphins.
3 other examples of peptide transmitters (except opioids)?
Substance P, neurotensin, vasoactive intestinal peptide (VIP).
3 other transmitters, not part of the aforementioned groups?
Purines (ATP, GTP, etc.)
Histidine
Gases - Nitric Oxide (NO).
Is NO stored?
No - synthesised in synaptic vesicles. Made as required.
What enzyme synthesises NO, and from what?
NOS, from arginine.
How does NO work?
Diffuses from nerve terminals into adjacent cells, forming covalent linkages to a multiplicity of targets.
How is NO presumed to inactivate?
Diffuse away.
2 types of transmitter receptor?
Ionotropic receptor (transmitter acts DIRECTLY on ligand gated ion channel to open channel). Metabotropic receptor (transmitter acts INDIRECTLY on G protein-coupled receptor).
Are ionotropic receptors always stimulatory?
Yes.
How quick are ionotropic and metabotropic receptors?
Ionotropic very fast - few milliseconds.
Metabotropic very slow - up to hours.
Sequence of events for transmitter receptors? (7)
- Agonist binds to receptor.
- GTP exchange for GDP on G protein α-subunit.
- G protein dissociates from receptor, then ligand.
- 3 subunits (α, β, γ) of G protein also dissociate.
- α-subunit activates ion channel.
- α-subunit inactivated by hydrolysis of GTP (to GDP) (by GTPase).
- α-subunit combines with β and γ subunits, attaching to receptor, which can then bind new agonist.
What else can G proteins act on, besides ion channels.
Enzyme targets - stimulating (Gs), or inhibiting (Gi).
What are the most common enzymes targeted by G proteins? And what are their corresponding second messengers?
Adenylate cyclase - cyclic AMP (cAMP).
Guanylate cyclase - cyclic GMP (cGMP).
Phospholipase C - inositol triphosphate and diacylglycerol.
Composition of ligand-gated receptors?
4 or 5 different subunits arranged around central pore in the membrane.
Four examples of ligand-gated receptors?
nicotinic acetylcholine, GABAA, glycine, 5-HT3 receptors.
How many subunits is the nicotinic receptor composed of?And how many different subunits are there in total generally? - what does this mean for the diversity of the receptors?
5.
17 generally. Means there are different combinations in skeletal muscle, autonomic ganglia, brain.
How do nicotinic ligand-gated receptors work?
α-subunit binds to acetylcholine, resulting in a conformational change opening the central ion channel.
What are G-protein coupled receptors composed of?
7 membrane spanning regions (α-helices).
Another name for G-protein coupled receptors?
7TM (seven transmembrane receptor).
5 examples of 7TMs?
Muscarinic acetylcholine, α-adrenergic and β-adrenergic receptors, all 5HT receptors apart from 5HT3, rhodopsin, olfactory receptors.
What do tricyclic antidepressants target?
(depression) block noradrenaline and serotonin uptake.
What do SSRIs target?
(depression, OCD) block serotonin uptake.
What does Valium and other benzodiazepines target?
(anxiety) activate GABA receptors.
What do MAO inhibitors target?
(depression, Parkinson’s) block breakdown of biogenic amines.
What does L-DOPA target?
(Parkinson’s) a dopamine precursor.
What do Acetylcholinesterase inhibitors target?
(Alzheimer’s) block breakdown of acetylcholine.
