Chemicals in the brain Flashcards
Synaptic transmission sequence
- An AP arrives to the presynaptic button, causing depolarisation of the membrane.
- Depolarisation opens voltage gated calcium channels, there is an influx of calcium ions.
- Calcium ions cause the migration of vesicles with NT to dock at the plasma membrane.
- Vesicles fuse with plasma membrane and release NT into the synaptic cleft.
- NT diffuses across the cleft and binds to specific receptors on the post-synaptic plasma membrane, initiating a response by opening or closing channels- inhibitory or excitatory.
- NT is removed from the synaptic cleft by glial cells or enzymes.
- Vesicular membrane is recycled from the presynaptic membrane.
Glutamate
- Where + What
- Function
- Synthesis
Amino acid NT, main excitatory NT found in the CNS
Function:
- Causes depolarisation of the post-synaptic membrane.
Synthesis:
- Made via the Kreb’s cycle from glucose.
- Converted from glutamine using glutaminase.
Re-uptake of glutamate
Into the presynaptic button using excitatory amino acid transporters (EAATs)
Relies on the electrochemical gradient formed by Na+/K+ ATPase
- 2Na+ co-transported with Glu.
Storage of glutamate
After synthesis in the cytoplasm, loaded into the vesicles via vesicular glutamate transporters (VGLUTs).
This relies on a proton gradient.
- Exchanges H+ for glutamate.
- H+ originally pumped into vesicles via H+- ATPase
GABA
- Function
- Speed of action
Gamma-aminobutyric acid
- An amino acid NT
Function:
Main inhibitory NT found in the brain.
Speed of action:
- Rapid, stored in small, clear core vesicles
Synthesis of GABA
Made from glutamate
- Using glutamic acid decarboxylase (GAD)
Storage of GABA
Pumped into vesicles using GABA transporter (GAT)
- Uses H+ gradient
Recycling of GABA
Re-uptake into the glial cells and neurones.
- Glial cells convert it t glutamine before transporting it back to neurone.
GABA is not recycled, it is made de novo whilst the vesicles are reformed.
The need for different types of neurotransmitters
Some neurotransmitters pass on information
- Glu, GABA
Others have modulating effect: active of inhibit entire circuits of neurone involved in specific brain functions.
- e.g Ach.
Glycine
- Function
- Storage
Inhibitory amino acid NT
- In the spinal cord and brain stem.
Storage:
- Transported into synaptic button using GABA transporter (GAT)
Vesicle docking
Influx of calcium ions from depolarisation
- Ca2+ binds to calmodulin kinase II
Calcium-bound calmodulin kinase II phosphorylates synapsin.
Phosphorylated synapsin is unable to bind to cytoskeleton, releases vesicles to active zone.
SNARE complex docks vesicle to plasma membrane.
Vesicle release
Mechanism= exocytosis.
- Synaptobrevin on vesicle membrane binds to plasma membrane proteins to form SNARE complex.
- SNARE complex pulls vesicular membrane to plasma membrane.
- Calcium influx binds Synaptotagmin.
- Calcium-bound synaptotagmin binds to SNARE complex and plasma membrane, causing them to fuse.
Botox
- Species
- Mechanism
- Uses
Poison from Clostridium botulinum species.
Mechanism
- Binds to SNARE protein, preventing release of Ach at neuromuscular junction.
- Causes muscle relaxation.
Uses:
Treatment for muscle spasm.
Tetanus
- Species
- Mechanism
- Uses
Clostridium tetani releases a toxin, acts as a poison.
Mechanism:
- Binds to SNARE protein, preventing release of GABA and Gly.
- Dis-inhibits cholinergic neurones
- Permanent muscle contraction.
Excitotoxicity
The damage or death of cells cause by excess excitatory stimulation.
- Due to excess Glutamate or too little GABA/glycine.
Constant stimulation causes excess influx of Ca2+ which increases digestive enzymes, causing cell death.
Cerebral ischaemia
- Mechanism
Lack of blood flow to the brain.
- Leads to excitotoxic cell death.
Metabolic events are disrupted
- Reversed Na+/K+ channels, pumps out glutamate into the synaptic cleft via transporters
GHB- gamma hydroxybutyrate
Date rate drug
Metabolite of GABA, converted back to GABA which administered.
Causes excess inhibition of neurones leading to sedation/ unconsciousness.
Congenital myasthenia syndromes
- What is the abnormality in neurones
Disruption of vesicle recycling.
LEMS mechanism of pathology
Caused by autoimmune attack on Ca2+ channels.
Prevents release of NT.
Latrotoxin
Poison that triggers vesicle fusion to the plasma membrane
- Excess release of NT
Differential release of NT
Low frequency stimulation = Only small molecular NT in small, clear core vesicles are release.
- Due to localised increase in Ca2+.
High frequency stimulation= BOTH small molecular and large molecular NT released
Serotonergic system
Modulatory system involved in:
- Sleep
- Pain
- Emotion
- Appetite
Small set of neurones arising from the brain stem (Raphe nuclei) are interconnected.
- Basal ganglia
- Thalamus + Hypothalamus
- Temporal lobe
- Cerebellum
Serotonin
- Function
- Storage + re-uptake + removal
Indolamine NT, released in the CNS and enteric NS
- Affects mood, sleep, appetite and pain.
Storage:
Pumped into vesicles
Re-uptake:
- Into presynaptic terminal using Serotonin transporters (SERTs)
Degradation:
- Monoamine oxidase in the cytoplasm
Synthesis of serotonin
Derived from amino acid tryptophan.
- Tryptophan —> 5-HTP
- Uses tryptophan hydroxylase. - 5-HTP —-> Serotonin
- Using 5-HTP decarboxylase
Dopamine
- Function
- Storage
- Re-uptake
- Degradation/ inactivation
Catecholamine NT made in presynaptic neurone cytoplasm.
Storage:
- Pumped into vesicles using vesicular monoamine transporters (VMATs)
Re-uptake:
- Into presynaptic terminal using (Dopamine transporters) DATs
Degradation:
- Monoamine oxidase (MAOs)
Inactivation:
- Catechol-o-methyl-transferase (COMTs)
Dopamine synthesis
Derived from tyrosine , in the cytoplasm.
- Tyrosine —> Dopa
- Using tyrosine hydroxylase (TH) - Dopa—> Dopamine
- Dopa decarboxylase.
Adrenaline and noradrenaline synthesis
In the vesicles:
- Dopamine—-> Noradrenaline
- Uses dopamine-beta-hydroxylase (DBH) - In cytoplasm:
NADR—-> adrenaline
- Using PNMT
- ADR stored into vesicles using vesicular monoamine transporter (VMAT)
Fluoxetine/ Prozac
- Drug type
- Mechanism
- Indications
Selective serotonin re-uptake inhibitor (SSRI)
- Blocks Serotonin transporter in presynaptic plasma membrane
Treatment:
- Depression
- OCD
Fenfluramine
- Drug type
- Mechanism
- Indications
Appetite suppressant
Mechanism:
- Stimulates serotonin release
- Inhibits serotonin re-uptake
Used to treat obesity.
MDMA
- Drug type
- Mechanism
- Indications
Psychoactive drug
Mechanism:
- Reverses Noradrenaline and Serotonin transporters on the plasma membrane.
- Increases release of these NT in the synaptic cleft
Currently being assessed to be used for PTSD.
Amphetamine
- Drug type
- Mechanism
- Indications
Stimulant drug
Mechanism:
- Blocks dopamine and Noradrenaline re-uptake
- Reverses the transporters on the plasma membrane for both NT.
Indications:
- Narcolepsy
- ADHD
Cocaine + Methyphenidate
- Drug type
- Mechanism
- Indications
Stimulants
Mechanism:
- Blocks Dopamine transporters, thus re-uptake
- Increases synaptic cleft dopamine.
Indications (Ritalin
):
- ADHD
- Narcolepsy.
Selegiline
- Drug type
- Mechanism
- Indications
Selective irreversible monoamine oxidase inhibitor
Mechanism:
- Blocks MAO, allowing more DA to be release on activation.
Indications:
- Early stage Parkinson’s disease
- Depression
- Dementia
Entacapone
- Drug type
- Mechanism
- Indications
Selective, reversible inhibitor of COMT (catechol-o-methyl transferase)
Mechanism:
- Inhibits COMT, preventing Dopamine inactivation.
- Increases available DA
Indications:
Parkinson’s disease.
Acetylcholine
- Function
- Synthesis
- Storage
Small molecule neurotransmitter.
- Main Modulatory NT in the brain
- Parasympathetic system
Synthesis:
Choline + Acetyl CoA
- Using Choline transferase
Storage:
- Pumped into vesicles using vesicular acetylcholine transporter.
Degradation and removal of Ach
Degradation:
Acetylcholinesterase enzyme in synaptic cleft.
- Choline is transported back into presynaptic terminal
Neostigmine
- Drug type
- Mechanism
- Indications
- Removal
An acetylcholinesterase inhibitor.
Mechanism:
- Prevents breakdown of Ach, prolongs its effect.
Treatment for myasthenia gravis (MG)
Broken down by proteases extracellularly
Neuropeptides NT
- Speed of action
- Function
- Removal
Released slowly but its effects last for a longer period than small molecules.
They are created in the soma and packaged there- quickly transported to the axon terminal.
Many functions, including: sensory functions.
Broken down by proteases extracellularly
NO as a NT
- Synthesis
- Action
- Removal
Soluble gas
- Made in the POSTsynaptic neurone
- Nitric oxide synthase (requires Ca2+- calmodulin)
Retrograde signalling
- made in post-synaptic neurone and diffuses between the synaptic cleft
Action:
- Activates guanylyl cyclase—-> cGMP
Removal
- Converted into an inactive form.
Endocannabinoids
- Function
Small lipids, act as a NT
Reduces GABA at certain terminals
Active compound in marijuana
