Neurochemistry Flashcards
Where does neurotransmitter synthesis occur?
In the presynaptic cell body / soma - it is then transported to the presynaptic knob via axonal transport
It is stored in vesicles here then released into the synapse through vesicle exocytosis
What does lock and key refer to with neurotransmitter binding?
That there is only one chemical conformation that a neurotransmitter can bind at a receptor site (note one neurotransmitter may bind to different receptor types/locations however at each site only one chemical conformation is allowed)
After being released into the synapse how does cessation of neurotransmitter action occur?
- Reuptake back to the presynaptic neuron via special transporters (monoamine transporters)
- Break down by enzymes (COMT or MAO-A)
- Removed by glia or plasma circulation (e.g. glutamate shuffle)
Name some ways that feedback of neurotransmitters is elicited?
- Presynaptic control of synthesis
- Regulation of release
- Blockade.regulation of reuptake
- Autoreceptor (presynaptic receptor) blockade preventing release
- Inhibition of release via postsynaptic receptors (different route)
Name amino acids that are also neurotransmitters?
GABA
Glutamate
Glycine
What neurotransmitters are classified as peptides?
Endorphins
Cholecystokinin
Neurotensin
Neuropeptide Y
Leptin
Ghrelin
Outline the three types of receptors and some examples associated with them?
Ionotopic - ligand gated channels. Neurotransmitter binding affects the likelihood of opening a transmembrane pore/channel:
- Fast responses but often short lived
- Examples are GABA-A, 5-HT3, NMDA
- Inhibitory neurotransmitter - Cl- enters cell or excitatory Ca2+ enter the cell
Metabotropic receptors are G-protein coupled. Binding here affects protein synthesis within the cell through 2nd messenger cyclase mediated activation (GTP, ATP). G-proteins can be stimulatory (Gs) or inhibitory (Gi). Some G-proteins activate phospholipase C. Examples include DA, 5-HT receptors.
Nuclear receptors. Have a cysteine rich DNA-binding domain, a ligand binding domain and an amino ternminal region. As the ligand binds the receptor becomes a transcripton factorr and binds to DNA via zinc fingers. Examples include glucocorticoid receptors, progesterone, androgen, Vitamin D, Triidothyronine. GR receptor in cytoplasm and moves to nucleus when bound, T3 and oestrogen remain in nucleus and bind hormones directly to the nucleus.
How is Dopamine made by which enzyme and how is it broken down?
Tyrosine –> L-Dopa –> Dopamine
Enzyme: Tyrosine hydroxylase
Broken down by MAO-A and MAO-B and Catechol-o-methyl transferase (COMT)
- MAO-B has more selective activity for DA whereas MAO-A has more activity for Serotonin and Noradrenaline
What is homovanillic acid?
The breakdown product of dopamine
What does cocaine inhibit?
Reuptake via the dopamine transporter
What are D1 like and D2 like receptors?
Dopamine receptors are all G-coupled receptors
D1 like receptors include D1 and D5:
- These receptors are Gs therefore stimulate adenylate cyclase. D5 in limbic distribution - 10 x higher dopamine activity. D1 is only found on the post synaptic area and cannot be antagonised.
D2 like receptors include D2, D3, D4:
- Clozapine has a high affinity for D4 but selective D4 antagonist don’t work as antipyschotics. D4 is mostly found in the frontal cortex of the brain.
How is noradrenaline made?
Tyrosine –> L-Dopa –> Dopamine –> Noradrenaline –> Adrenaline
As for dopamine tyrosine hydroxylase is the rate limiting step
Dopamine-b-hydroxylase converts dopamine to noradrenaline
Phenylethanolamine-N-methyltransferase then converts noradrenaline to adrenaline
Which enzymes break Noradrenaline down?
MAO-B and COMT
What is noradrenaline broken down to?
MHPG and VMA
- 3-methoxy-4-hydroxyphenylglycol (centrally)
- Vanillyl mandelic acid (peripherally/endocrine system)
What are the Noradrenaline receptors?
alpha-1: post synaptic and phospholipase C coupled
alpha-2: pre synaptic and are Gi coupled
Beta-1: high affinity for noradrenaline
Beta-2: high affinity for adrenaline
- Both types of Beta-receptor are Gs coupled and are found in high numbers in locus coerlus.
How is Serotonin made?
Tryptophan - 5-hydoxy L-trytophan –> serotonin
Rate limiting step is availability of Trptophan
Then synthetic enzyme involved is Tryptophan hydroxylase
What is 5-hydroxyindoleacetic acid (5-HIAA)
The breakdown product of serotonin
What is the only serotonin receptor not to be G-protein coupled?
5-HT3 - ligand gated (ionotropic) found in abundance in the gut and associated with motility (responsible from sickness of SSRI)Outlin
Outline the location and function associated with the following receptors?
a) 5-HT1A
b) 5-HT1B
c) 5-HT1D
d) 5-HT2A
e) 5-HT2B
f) 5-HT2C
g) 5-HT3
h) 5-HT6
i) 5-HT7
a) postsynaptic, Gi, anti-D (agonise), anxiolytics (partial agonise). associated with an anti-D response and sexual behaviour
b) presynaptic, Gi, implicated in aggression behaviour
c) pre + postsynaptic, Gi, antagonism is beneficial for antimigraines
d) 5-HT2A phospholipase C. Psychedelics lead to agonism/partial agonism. Antipsychotics antagonise. Function useful in working memory. Expressed in platelets and smooth muscle
e) 5-HT2B stimulation may cause cardiac valvular fibrosis (dexfenfluramine)
f) 5-HT2C agonism leads to anxiogenic and anorexic effects
g) 5-HT3 antagonism leads to antiemetic effects
f) 5-HT6 are implicated in anti-depressants and antipsychotics
g) 5-HT7 is involved in the regulation of circadian rhythms
What is DDC and which neurotransmitters is it implicated in?
DOPA decarboxylase (DDC) is an enzyme:
It converts L-DOPA to dopamine through decarboxylation
It converts 5-OH tryptophan to Serotonin
Which dopamine receptors can be located presynaptically
D2 and D3
D2 and D3 binding inhibits further dopamine release due to their Gi effects (inhibit adenylate cyclase)
What type of receptor is an NMDA receptor?
Ionotropic
- Although NMDA receptors are G-protein coupled neurotransmitter binding (Glutamate and Glycine) leads to the opening of the pore with ions entering.
What does the endoplasmic reticulum do?
Create lipids (inc. phospholipids), synthesis of steroid hormones, breakdown of lipid-soluble toxins in Liver cells and control of calcium release in smooth muscle cell contraction.
The ER is located in cells across the body and made up of a network of vesicles and tubulues.
Where are dopamine receptors located?
D1 & D2 - predominately caudate and putamen
D3 - nucleus accumbens
D4 - PFC
D5 - Hippocampus
D3 and D4 are more located (mesocortical, mesolimbic and hypothalamic)
What are dopamine and noradrenaline?
Catecholamines
What enzyme inactivates the function of GABA
GABA transaminase
What circuits may underlie the pathogenesis of huntingtons?
GABA circuits
What drug does Khat mimic?
Amphetamines
In Alzheimer’s what happens to Acetylchole-esterase (enzyme that breaks ACh down) and choline acetylene transferase (precursor)
Both decrease - this is due to deformation of ACh neurons
Which enzyme is involved in the catabolism of GABA?
Transaminase
What are the precursors to Acetyl Choline?
Choline
Acetyl-coenzyme
Synthesised by choline acetyltransferase
The rate limiting step is the availbility of choline
Name some processes that Acetlycholine is used in?
Modulating arousal
Rapid eye movement sleep
Pain
Learning and memory
Thirst
Mediating the parasympathetic nervous system
How do muscarinic and nicotinic receptors compare?
Both are bound to by acetylcholine
Muscarinic are more located with the CNS
M1-M5
All are G protein coupled
Nicotinic receptors are ligand gated ion channels (ionotropic)
What disorders is Acetylcholine implicated in?
Dementia - reduced ACh function
Parkinson’s may impact the balance of DA
Is there reuptake of ACh?
No - it gets broken down then it is the choline that is re-uptaken
What is the precursor to GABA?
Glutamic acid (glutamate)
Synthesised using the enzyme glutamate decarboxylase
The rate limiting step for the synthesis of GABA is the catalysis of glutamate decatboxylase
GABA gets broken down by GABA transaminase to glutamate then succinic acid
How do GABA-A and GABA-B channels differ?
GABA-A is ionotropic - binding of GABA opens chloride channels leading to hyperpolarisation of the cell. GABA A is made from 4 protein subunits for which there are 14 subunit subtypes
GABA-B is G protein coupled - baclofen is a selective agonist to GABA B
How is GABA reuptaken?
Both presynaptically and by surrounding glial cells.
Temperature and ion-processes can influence this (Tiagabine) can inhibit GABA reuptake
What disorders is GABA implicated in?
Anxiety
Huntingtons
Alcohol
Epilepsy (GABA leads to seizure cessation)
Name some precursors to Glutamate?
2-oxoglutarate and aspartate by aspartate aminotransferase
Glutamine by glutaminase
2-oxoglutarate by orithnine aminotransferase
Name the enzyme that makes glutamate?
Glutaminase
What is glutamate broken down to?
Glutamate dehydrogenase
Glutamine synthetase
The prodoucts are:
- Glutamine
- Alpha ketoglutarate
How is glutamate reuptaken?
By glial cells that convert to glutamine
Name some functions of Glutamate?
Oxidation pathway
Ammonia pathway
Memory acquisition and long term potentiation (plasticity through NMDA receptors)
Precursor to GABA
Epilepsy and ischaemic brain injury
What receptors does glutamate act on?
Metabotopric (8 in total divided into 3 groups):
- Group 1 mGluR1 & mGLuR5 - link to phospholipase C
Ionotropic:
- Non-NMDA - kainate binding or AMPA type
- NMDAL Subunits with binding sites for glutamate, glycine, D-cylsine, phencyclidine, Magnesium, Zinc
Where does glycine act?
Non-strychnine-senstive glycerine receptors:
- At these receptors glycine is the mandatory adjunctive neurotransmitter for glutamate receptors
- This is the excitatory glycine site on NMDA receptors
Strychnine-sensitive receptors is the inhibitory receptor in the spinal chord where glycine acts on its own
What is bitopertin?
Bitopertin is an experimental glycine reuptake inhibitor.
Facilitating glycine transmission has shown some early promise in targetting -ve symptoms of Schz
What are the two endogenous endocannabinoids?
Anandaminde - analgesia, reduces ocular pressure and lowers activity
2-arachnidonylglycerol
(these are made from arachidonic acid and ethanolamine
What are the two cannabinoid receptors?
CB1 (central)
CB2 (peripheral)
Bind tetrahydrocannabinol which is the active ingredient of THC
Why is the SNP on chromosome 11p13 important?
It represents the Valine to Methionine substitution at codon 66 Val66Met - this SNP shows down regulation of BDNF
Mice with Val66Met have reduced BDNF activity, are more anxious and have impaired hippocampal activation
BDNF is upregulated by SSRIs, ECT and ketamine.
Leads to trophic effects of serotonin and noradrenaline neurons.
What is the neurotrophin hypothesis?
Neurons compete against each other - the ones that survive have high affinity to nerve growth factors (BDNF, NGF, Neutrophin 3, Neurotrophin 4).
Incorrect targeting of axons may also lead to apoptosis.
What is aberrant salince?
The ideas that mesolimbic dopamine acts to attach meaning to external stimulus or internal thoughts. Therefore in psychosis abnormal meanings are made (delusions) due to this hyperactivity.
Antipsychotics may reduce salience of stimuli allowing for psychological explanations
