Neurotransmitters and Pharmacology Flashcards
What are the adaptations and functions of the dendrites in neurones
Dendrites have spines which increase the surface area for the receipt of information from the other neurones etc. So the dendrites are information receptors
Function of soma/ cell body in the neurone
Integration of the signals received
Function of the axon
Rapid transfer of the action potential
Where are neurotransmitters release from
The synaptic terminal
Neurotransmission is restricted to specialised structures called …
Synapses
What are the three stages of synaptic transmission
1) Biosynthesis, packaging and release of neurotransmitter ( which is packed into vesicles )
2) Receptor action
3) Inactivation of neurotransmitters to allow for the system to work effectively
The three classes of neurotransmitter present
Amino acids
Amines
Neuropeptides
Amino acid neurotransmitter
Glutamate
Gamma-amimobutytic acid (GABA)
Glycine (Gly)
Amines neurotransmitter
Noradrenaline ( NA)
Dopamine (DA)
Neuropeptide neurotransmitters
Opioid peptides
Glutamate
Single most important amino acid in brain , normally excitatory transmitter
GABA
Most important inhibitory transmitter in brain
Glycine
Inhibitory neurotransmitter in spinal cord
Noradrenaline
Involved in sympathetic and parasympathetic nervous system
Opioid peptides
Endorphins etc
Step 1 of CNS synapse activation
AP
Step 2 of CNS synapse activation
Depolarisation of nerve terminal ( sodium and potassium ion channels start working etc )
Step 3 of CNS synapse activation
Voltage gated calcium channels open and calcium enters into presynaptic nerve terminal down the concentration gradient
Step 4 of activation of CNS synapse
Calcium ions stimulate the release of neurotransmitters into the synaptic cleft
Step 5 of activation of CNS synapse
Neurotransmitters bind to receptors on post synaptic neurone. In the case of an excitatory synapse, they cause sodium ions to go into cell and stimulate another AP
Step 6 of activation of a CNS synapse
Reputable of neurotransmitters into presynaptic nerve terminal where it is packaged into vesicles
Or broken down by enzymes
What enzyme works to break down ACh
Acetylcholine is broken down by acetylcholinesterase which sits in cleft and so inactivates it
Step 7 of activation of CNS synapse
Sodium potassium transported restores status before another AP arrives
What conc of calcium is needed to be reached inside the cell for the neurotransmitter to be released
200 microM , resting cellular calcium conc is less that 1 microM
Quanta
Packets of 4000-10000 molecules of neurotransmitters
Neurotransmitter release
Activation of transmitter release is calcium dependent and required RAPID transduction
Membrane depolarisation Calcium channels open Calcium influx Vesicle fusion Vesicle exocytosis Transmitter release
How do rapid release rates occur
Synaptic vesicles are filled with neurotransmitter and docked in the synaptic zone
Special proteins on the vesicle and presynaptic membrane enable fusion and exocytosis ( called vesicular proteins )
What are proteins on the vesicles called
SNARE proteins like synapse in ,synaptobrein and SNAP25
They mediate the process of exocytosis and the release of the neurotransmitter
Name some neurotoxins
Vesicular proteins are targets for neurotoxins
- alpha latrotoxin
- tetanus toxin
- botulinum toxin
Alpha tarotoxin
From black widow slide and stimulates the transmitter release until depletion and so none is left. It focuses on cholinergic terminal which releases ACh. Eventually you see muscular paralysis
Examples of zinc dependent endopeptidases
Tetanus
Botulinum toxin
What do zinc dependent endopeptidases do
Inhibit transmitter release
Tetanus toxin ( Ctetani)
Causes spasms and paralysis - inhibits the release of 2 main neurotransmitters GABA and glycine which are inhibitory transmitter release
Bolulinum toxin ( C botulinum)
Causes flaccid paralysis due to the complete muscle relaxation . It is a bichain molecule. First part of molecule binds to cholonergic NT terminal.
Second chain penetrates nerve terminal and interacts with vesicle protein so cleaves peptide bonds and inactivates vesicular protein and so NT cannot be released
Botox
Causes relaxation of muscle and smoothing of brow to stop release of ACh
What can botulism cause
Nasty form of food poisoning and can cause resp arrest and death
Transmitter release requirements
Calcium dependent
Transmitter containing vesicles are to be docked on ore synaptic membrane
Protein complex formation between vesicle, membrane and cytoplasmic proteins to enable both vesicle docking and a rapid response to calcium ion entry leading to membrane fusion and exocytosis
ATP and vesicle recycling - pumps which fill vesicle with neurotransmitters are ATP requiring pumps
Ion channel linked receptor
Mediate all fast excitatory and inhibitory transmission in CNS( msec)
Excitatory ion channel linked receptor
Sodium ions
Inhibitory ion channel linked receptor
Chloride ions
Glutamate receptor
Glutamate binds and stimulates and opens the receptor allowing sodium ions to enter cell and stimulate an action potential
G Protein coupled receptor
Slow response ( secs/mins/hrs)
What is usually the effector in G protein coupled receptors
Enzymes ( adenyl cyclase, phosplipase C, cGMP-PDE) or channels ( calcium or potassium ) . When stimulated by agonist, Binds to G protein which then binds to AC ( enzyme)
This may stimulate / inhibit enzyme
What does a G protein coupled receptor consist of
7 alpha helical transmembrane proteins
Examples of Ion channel linked repceptors inCNS
Glutamate , GABA
Example of ion channel linked receptor at neuromuscular junction
Acetylcholine at nicotine’s receptors ( links to sodium ions)
Examples of G protein coupled receptors at the CNS and PNS
ACh atmuscarinic receptors ( heart - stimulates vagus nerve which decreases heart rate due to ACh) , dopamine, noradrenaline , serotonin ( 5 HT) , and neuropeptides ( enkephalinn)
Nicotinic receptors are which kind of receptors
Ion channel linked
Muscarinic receptors are which kind of receptor
G protein linked
Influx of chloride ions lead to
Hyperpolarisation . IPSP produced
Influx of sodium ions leads to
Depolarisation . EPSP produced
Two types of glutamate receptors
AMPA and NMDA
AMPA receptors
Majority of fats excitatory synapses,
Rapid onset, offset and desensitisation
Only sodium ions can enter
NMDA receptor
Dosimeter and calcium ions can enter
Slow component of excitatory transmission
Serve as coincidence detectors which underlie learning mechanisms and memory processes
What does coincidence receptor mean
Needs another incoming signal to stomata signal and glutamate
Which part of the body has an increased density of NMDA receptor
Hippocampus ( involved in short term memory)
Excitatory glutamate synapse process
1) glutamate synthesised from glucose via TCA cycle and transamination
2) glutamate reversibly binds to post synaptic receptors ( NMDA and AMPA ion channels )
3. Rapid uptake of glutamate by excitatory amino acid transporters - reuptake of inactivated gluamate
4. Glutamate is emzymatically modified by glutamine sythetase to glutamine in glial cells
What happens to the glutamine in glial cells
Glutamine is released by glial cells and can then be taken up by presynaptic membranes to make glutamate, referred to as glutamate-glutamine cycle
Seizures
Abnormal cell firing leads to seizures associated with excess glutamate in the synapse. Uncontrolled glutamate release leads to increased spiking on EEG , increased electrical activity in brain and the seizures and physical effects of convulsions
As glutamate decreases, glutamine increases and decreases . Excess glutamate is metabolised to glutamine
What does refractory mean
Doesn’t respond to treatment
Difference between seizures and epilepsy
Single seizure can be due to high temp etc but recurrent seizure are classed as epilepsy
Inhibitory form of GABA synapse
1) GABA synthesised by de carboxylation of glutamate by glutamic acid decarboxylase ( GAD)
2) GABA reversible binds to post synaptic receptors ( linked to ion channels)
3) rapid reuptake of GABA by GABA transporters ( GATs)
4) GABA enzymatically modified by GABA transaminase ( GABA-T) to succinic semialdehyde ( glial cells and GABA nerve terminals )
What happens to the succinic semialdehyde
Broken down to succinate which is put back into TCA cycle
Epilepsy may be due to
GABA receptors not working well
Structure of GABA receptor
Pentameric organisation provides pharmacologically imp binding domains
Drugs facilitating GABA transmission are
Anti-epileptic- barbiturates and benzodiazepines
Anxiolytics
Sedative
Muscle relaxant
