Lecture 7 NS - Neurotransmitters Flashcards
What is necessary for neurotransmission to occur?
Release of neurotransmitters and their interaction with postsynaptic receptors
What are the 3 stages of synaptic transmission?
Transmitter released from 1st cell, synaptic activation of second cell and signal integration/conduction by 2nd cell
What are the main points about synaptic transmission?
Rapid timescale, diversity, adaptability, plasticity, learning and memory
What is the structure of the cell body?
How large are synapses?
20-100 nm
Where are NT contained?
Synaptic vesicles
Why are mitochondria present?
Synaptic transmission is a very high energy process
What is the postsynaptic density?
Electron dense material underneath synapse with signalling proteins which mediate a number of pathways which happen in response to cell activation
What are the 3 stages of synaptic transmission?
Biosynthesis, packaging and release of NT, receptor action and inactivation of NT
What are neurotransmitters?
Provide enormous diversity in variety of transmitter and their receptors -> may mediate rapid or slower effect
What are the most important NT?
Amino acids (glutamate (stimulates), GABA (inhibit), glycine), amines (NA, DA) and neuropeptides (opoid - endorphins)
How do NT vary in abundance?
From mM to nM CNS tissue concentrations
How do neurons produce diverse functional responses?
Neurons receive multiple transmitter influences which are integrated
How is a CNS synapse activated?
Action potential arrives at nerve terminal which depolarises it, causing entry of Na and outflow of K -> Ca channels open and enter into cell which triggers NT release into the synapse which activates its receptors, to open Na channel, continuing the AP -> NT needs to be regulated which is controlled by desensitisation of receptors and removal of NT from synapse via transporters which rapidly remove NT from synapse -> NT is accumulated into vesicle ready to go, with Na pump pumping Na out to return to membrane potential
How is ACh removes from the synapse?
ACh esterase breaks it down, present on postsynaptic membrane
What are the essential components of synaptic transmission?
Restricted to specialised structures, fast, Ca is essential for NT release and synaptic vesicles provide source of NT
How can rapid release of NT occur at the synapse?
Synaptic vesicles are filled with NT and docked in the synaptic zone ‘primed’ -> interaction between synaptic vesicle and synaptic membrane proteins allow rapid response -> Ca entry activated Ca sensor in protein complex
What are some neurotoxins that target vesicular proteins?
Tetanus (paralysis) and botulinum toxin (Flacid paralysis)
What is necessary for transmitter release?
Transmitter containing vesicles to be docked on presynaptic membrane; protein complex formation between vesicle, membrane and cytoplasmic proteins to enable vesicle docking and rapid response to Ca entry; ATP and vesicle recycling
What is NT action defined by?
Receptor kinetics
What are the 2 types of NT receptor?
Ion channel receptor and G-protein coupled receptor
What is the difference between ion channel receptor and G-protein coupled receptor?
ICR: fast (msecs), mediates all fast excitatory and inhibitory transmission -> just a channel. GCPR: slow (s/min), effectors may be enzymes (PLC) or channels (K or Ca) -> made up of receptor, g-protein and effector
What are some examples of ion channel receptor?
CNS: glutamate, Gamma amino butyric acid (GABA). NMJ: ACh at nicotinic receptors
What are some examples of G-protein coupled receptors?
CNS/PNS: ACh at muscarinic receptors, DA, NA, 5-hydroxytryptamine and neuropeptides
What are ion channel linked receptors?
Rapid activation, diversity and rapid information flow, multiple subunit combinations-distinct functional properties
What are the 4 different ion-channel linked receptors?
Nicotinic cholinergic receptors, glutamate, GABA, glycine receptors -> GLUR (Na), GABAR (Cl), GlyR (Cl)
What is the difference between inhibitory and excitatory NT receptor?
GluR -> Na entry, so depolarisation enters, so EPSP, GABAR -> Cl entry so hyperpolarisation so threshold for response has been changed
What are the 2 types of glutamate receptors?
AMPA receptor and NMDA receptor
What does the AMPA receptor do?
Na+. Majority of FAST excitatory synapses w/rapid onset, offset and desensitisation
What does NMDA receptor do?
Na+ and Ca2+. Slow component of excitatory transmission, serving as coincidence detectors which underlie learning mechanisms
What does the Ca that enters NMDA do?
Modifies the AMPA receptor potentiating AMPA receptor response and activates protein synthesis which modifies synapse formation
What occurs in an excitatory CNS synapse mediated by glutamate?
Glutamate made from glucose in TCA -> released in synapse and reacts with GLUR, letting Na or Na/Ca in. To remove Glut from the synapse, excitatory a.a. transporters present on nerve and glial cells take up the glut -> in glial cell glut is broken down [glutamine synthetase] into glutamine, which is inactive
What is epilepsy?
Common neurological condition, characterised by recurrent seizures due to abnormal neuronal excitability (leading to increased glutamate release) -> despite advances in modulating seizure generation and propagation, the disease is disabling -> 30% refractory to treatment
How do CNS inhibitory synapses mediated by GABA work?
GABA is synthesised from glutamate by GAD, then released and acts upon GABAR which has an inhibitory effect due to Cl entering the post-synaptic cell -> inactivated by GABA trans-aminase in glial and presynaptic cell into succinate semialdehyde
Why is succinate semialdehyde helpful?
It can enter the TCA cycle via a GABA shunt
How is the GABA receptor targeted by pharmacological components to dampen down excitatory activity?
What do benzodiazepines do?
Increase fequency of channel opening
What do barbiturates do?
Increase duration of channel being open
What is the focus of epilepsy treatment?
Damping down excitatory activity by facilitating innhibitory transmission
Where do benzodiazepines and phenobarbital act upon in the GABA synapse?
On GABA[A] receptor on 2 different sites, increasing inhibitory activity of GABA
Where does tiagabine act upon in the GABA synapse?
It is a competitive inhibitor of the GABA transporter, so more GABA is available for receptor binding on the surfaces of post-synaptic cells
Where does vigabatrin act upon in the GABA synapse?
It acts upon GABA-T (enzyme) to prevent the break down of GAB, leaving more GABA available for exocytosis into synapse
