2.5 - Neurotransmitters and Pharmacology Flashcards
1
Q
What is synaptic transmission?
A
- information transfer across the synapse requires release of neurotransmitters and their interaction with postsynaptic receptors
- electrical transmission through first neurone –> chemical transmission at synapse –> electrical transmission at second neurone
1. NT released from 1st cell
2. synaptic activation of 2nd cell
3. signal integration and signal conduction by 2nd cell
4. signal transmitted to effectors / subsequent neurones
2
Q
What are the key features of synaptic transmission?
A
- rapid timescale
- underlies diversity of CNS function e.g. in plasticity, and learning and memory
3
Q
What is the structure of a neurone?
A
- soma (cell body) - involved in information reception through dendrites (extensions of soma) - integrates and processes information received and decides action
- dendrites have spines which increase surface area for information reception from other neurones
- soma integrates information coming in then transfers an AP down axon to synaptic terminal very rapidly
- causes NT release from synaptic terminal for communication between neurones
- information reception –> integration –> rapid transfer (AP)
- each neurone may receive and make several hundred/thousand synapses
4
Q
What are the three main components of a synapse?
A
- presynaptic nerve terminal
- synaptic cleft - gap of around 20-100 nm
- postsynaptic region (dendrite or cell soma)
5
Q
What types of neurotransmitters are there?
A
- enormous diversity in variety of NTs and their receptors
- amino acids e.g. glutamate, gamma-aminobutyric acid (GABA), glycine
- amines e.g. noradrenaline (NA) and dopamine (DA)
- neuropeptides e.g. opioid peptides like endorphins
- these vary in abundance from nM to mM CNS tissue concentrations
- neurons receive multiple transmitter influences which are integrated to produce diverse functional responses
- may mediate rapid (us to ms) or slower effects (sec/min/horus)
6
Q
What are the three stages of synaptic transmission?
A
- biosynthesis, packaging and release of NT from presynaptic terminal
- receptor action at postsynaptic region
- inactivation of NT
7
Q
1) Biosynthesis, packaging and release of NT from presynaptic terminal
A
- neurone activated, AP fired and propagated –> AP arrives down axon and spreads across nerve terminal to depolarise it
- rapid Na+ influx then K+ efflux at terminal
- activates VGCCs = Ca2+ floods into presynaptic terminal due to large concentration difference –> rapid response to influx occurs called electrochemical transduction
- NT is loaded into vesicles (through protein pumps on vesicle surface) and Ca2+ influx causes them to be docked onto presynaptic membrane via their SNARE vesicular proteins (e.g. synapsin, synaptobrevin, SNAP-25)
- vesicles primed then fuse with membrane (via vesicular proteins and other proteins on presynaptic membrane) –> exocytotic release of NT into synaptic cleft
- empty vesicles bud off inside presynaptic terminal to form new vesicles and reused for more NT release when next AP arrives
8
Q
What is another use of vesicular proteins? (neurotoxins)
A
- provide targets for neurotoxins that interfere with NT release process
- alpha latrotoxin (from black widow spider) that stimulates NT release to depletion from presynaptic membrane - focuses on and binds to cholinergic terminals –> massive release of ACh until depleted –> muscular paralysis
- Zn2+ dependent endopeptidases are toxins that inhibit NT release:
- tetanus toxin (produced by C. tetani) causes spasms and paralysis as it inhibits release of GABA and Gly (two inhibitory NTs in CNS)
- botulinum toxin (produced by C. botulinum) causes flaccid paralysis –> paralysis due to complete muscle relaxation:
- made of two chains: first binds to cholinergic nerve terminal and second penetrates terminal and interacts with vesicular proteins and cleaves the peptide bonds = inactivating them
- this toxin causes bad food poisoning, same toxin used in Botox as it causes muscle relaxation = smooth out facial features to make them look younger
9
Q
2) Receptor action at postsynaptic region
A
- NT rapidly diffuses across synaptic cleft and makes contact with postsynaptic receptors
- in an excitatory synapse, the receptors allow Na+ influx into postsynaptic cell –> depolarisation –> AP generated
- in an inhibitory synapse, receptors allow Cl- influx into postsynaptic cell –> hyperpolarisation
10
Q
What are ion channel-linked receptors?
A
- give fast response (us to ms)
- mediate all fast excitatory and inhibitory transmission
- made of multiple (usually 5) different subunits and this combination gives distinct functional properties
- Na+ channel-linked receptors responsible for depolarisation thus excitatory transmission
- Cl- channel-linked receptors responsible for hyperpolarisation thus inhibitory transmission
- CNS: glutamate receptor (GluR - linked to Na+ channel), GABA receptors (GABAR - linked to Cl- channel), glycine receptors (GlyR - linked to Cl- channel)
- NMJ: ACh acts at nicotinic cholinergic receptors (nAChR - linked to Na+ channels) on skeletal muscle fibres
11
Q
What are G-protein-coupled receptors?
A
- give slow responses (secs/mins)
- NT binding causes binding of receptor to G-protein which binds to effector
- effectors may be enzymes (adenylyl cyclase, phospholipase C, cFMP-PDE) or ion channels (e.g. Ca2+, K+)
- CNS and PNS: ACh at muscarinic receptors (e.g. in heart), DA, NA, serotonin (5HT) and neuropeptides like enkephalin
12
Q
What post-synaptic potentials do we see following excitation and inhibition?
A
- excitatory NT receptors - we see excitatory postsynaptic potential (EPSP) - Na+ influx causes increase in Em from resting potential to around -50/-40 mV –> this then returns to normal over a few ms
- e.g. glutamate causes this - principle excitatory NT in brain
- inhibitory NT receptors - we see inhibitory postsynaptic potential (IPSP) - Cl- influx causes decrease in Em from resting potential to more negative –> this then returns to normal over a few ms
- e.g. GABA causes this - principle inhibitory NT in brain
- there is normally a balance between excitation and inhibition
13
Q
What types of glutamate receptors are there?
A
AMPA receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)
- majority of fast excitatory synapses
- rapid onset, offset and desensitisation
- permeable to Na+ ions
NMDA receptors (N-methyl-D aspartate)
- slow component of excitatory transmission
- serve as coincidence detectors which underlie learning mechanisms - means they need another signal before glutamate can bind - hippocampus has high density of these receptors
- permeable to Na+ and Ca2+ ions (Ca2+ acts as 2nd messenger)
- most glutamate synapses have both types of receptors and require co-agonist glycine
14
Q
3) Inactivation of NT
A
- NT reuptake into presynaptic nerve occurs where it is reloaded into synaptic vesicles to be reused as NT
- enzyme degradation of NT within synaptic cleft e.g. ACh is broken down by acetylcholinesterase (bound to basolateral membrane in synaptic cleft)
- Na+K+ATPase restores resting membrane potential at presynaptic terminal - extrudes Na+ ions and brings back in K+ ions –> these ion pumps work independently of NT reuptake systems
15
Q
What happens in an excitatory glutamate synapse?
A
- Glu synthesised from glucose via TCA cycle and transamination in presynaptic terminal
- Glu loaded into vesicles, AP arrives, depolarises membrane, Ca2+ influx, exocytosis and diffusion of Glu
- Glu reversibly binds to postsynaptic receptors linked to ion channels (AMPA and NMDA) –> response
- Glu inactivated by rapid uptake by glial cells that envelope synapses by excitatory amino acids transporters (EAATs) on their surface (also some reuptake into presynaptic terminal)
- once in glial cell, Glu enzymatically modified by glutamine synthetase to glutamine in glial cells
