Lecture 9 – NEUROTRANSMITTERS Flashcards
Neurotransmitters:
- Receptor binding
- Neurotransmitter diversity
- Receptor activation/ effects
Diagram shows a signal diffusing across the cleft at around 20-30nm creating a delay, this is why you use chemicals
Receptors:
- Membrane-spanning proteins compromising a number of subunits (diagram gives an idea for ligand specificity)
- Ligand binding (substrate) induces a conformational change in receptor by activating it which has a docking site to match shape
- Lock-and-key hypothesis for binding of neurotransmitter
- If the concentration of drug is increased too much then side effects become apparent as it begins to bind to receptors that it shouldn’t do
- Can be analysed using Vmax and Bmax
Agonists and Antagonists:
- Used to understand synaptic function
- Was a major role for drug discovery
- An allosteric modulator binds the receptor at a different site to alter how receptor responds to ligand (compound that binds to a receptor very distinct from the active site, and by doing so changes the shape)
- Can get 100% agonist activation as a curve would flatten out at the end
- Partial activation will never show 100% activation because it’s not as specific
- An antagonist binds locking the natural ligand out of its binding site so a lot of toxins would do this (block neurotransmitter systems)
Nicotinic Acetylcholine Receptor:
LIGAND-GATED ION CHANNEL
Nicotine from the plant eaten by animals
- Membrane-spanning protein
- External face is where the ligand would bind
- Internal face is where the ions will come out and into the cell
- Five subunits (2-alpha, 1-beta, 1-delta, 1-epsilon, 1-gamma) arranged to form a pore
- Specificity of how the receptor works depends on subunits
- 2Ach (ligands) binds to 2-slpha subunits to open the channel
- when substrate binds, causes rotations allowing the subunits to slip in or out and opens a pore which is lined with negative charges (in diagram)
- Na+ and K+ flow down their electrochemical gradient as Na+ goes in (bigger difference)and K+ leaks out
- Membrane depolarises (epsp)
- There is a huge diversity of subunits and hence receptors
Classical
- Acetylcholine
- Dopamine
- Serotonin (5-hydroxytryptamine)
- Adrenaline (epinephrine)
- Noradrenaline (norepinephrine)
- Histamine
- L-Glutamic acid
- γ-amino-butyric acid (GABA)
Neuropeptides
- Substance P(pain fibres)
- Endorphins (warm glow)
- Enkephalins (circadian rhythms)
- Vasopressin (love hormone)
- Oxytocin
- Slow-acting hormones
Others
- NO (nitric oxide)
- Don’t have receptors in membrane as can easily pass through
- Adenosine (ATP breakdown)
- ATP
- Fast-acting and have receptors on cell surface
Identification of a Neurotransmitter:
- Must be synthesised by the neuron
- Must be present in synaptic terminal at sufficient concentrations (must be above its neighbours)
- Must be released on presynaptic stimulation
- Exogenous application to postsynaptic cell evokes a response that mimics the response from the endogenous signal
- Mechanism exists for its removal from synaptic cleft
Amino acids:
- e.g. glutamate; glycine; -aminobutyric acid (GABA) (synaptic vesicles, 50 nm)
- glutamate - excitatory
- GABA – inhibitory (but there are exceptions)
- these two are the main transmitters of the mammalian brain
Amines: e.g. acetylcholine (ACh)
- dopamine; noradrenaline; serotonin (5-HT) (synaptic vesicles)
- acetylcholine – neuromuscular junction, brain
- dopamine – movement
- serotonin (= 5-HT) – sleep, appetite, arousal, sex
- these change how other transmitters work
Peptides: (contain amino acids or the amines at higher frequency of AP – how active the neuron is)
- e.g. enkephalin; substance P; neuropeptide Y (dense-core secretory granules, 100 nm)
- enkephalin - opiate
- substance P – pain
- slow-acting and travel large distances
- neuro-modulators
Dale’s Principle
localisations (1 amine +1 or more peptides in the same terminal)– e.g. amino acid and peptide which shows that the Dale’s Principle no longer holds (each synaptic terminal has 1 neurotransmitter)
Synthesis of Neurotransmitters:
Amines and Amino Acids – terminal
Choline you take in from your diet and acetylcholine enzyme A which comes from the Kreb’s cycle
1. Enzymes and transporters in terminal – taken up by vesicular transporter (vesicular ACH)
2. Enzymes convert precursors into neurotransmitter in cytosol (secondary transporter is used)
3. Transporters load neurotransmitter into vesicles
4. Vesicle is pumped with lots of protons so a gradient form (2 protons out and 1 Ach in)
5. A very high energy cost – very demanding
6. Shorter the route, the less energy demanding it is to synthesise transmitter
7. Choline is less potent of binding to the receptor and activating it than Acetylcholine, thus is not in the diet, cigarettes however, release Ach
Removal of neurotransmitter from the synaptic cleft:
This is important for effective signal transmission and avoids desensitisation
¥ Diffusion: e.g. small amines and amino acids used as the best measure transmitters
¥ Reuptake: specific neurotransmitter transporter proteins in terminal and glial membranes. e.g. choline transporter
¥ Enzymatic degradation in cleft - followed by uptake of precursors e.g. acetylcholinesterase (AChE)
Acetylcholine Receptor:
nicotinic from nicotine plant
- ionotropic because they have an ion channel as part of the receptor
- muscarinic from the cell walls of mushrooms (could die if u pick the wrong ones)
- when activated, cations can flow through
- receptors are metabotropic which means they couple with G-proteins (GPCRs)
- this one isn’t an ion channel and affects ion permeability – slower
