Neurotransmitters Flashcards
What does neurotransmission require?
release of neurotransmitters and interaction with post synaptic receptors
What are the 3 phases of synaptic transmission?
1 - transmitter synthesised, packaged and released from 1st cell into synapse
2 - synaptic activation of 2nd cell, signal integration and signal conduction
3 - inactivation of NT
What are the key traits of neurotransmitter?
rapid (2ms/200micros) - chemical transmission allows rapid transmission of lots of info over small area of contacts
diverse
adaptable
plastic
learning and memory
What is found on dendrites?
protrusions (spines)
that increase number of possible inputs to a nerve cell
What is the function of inputs into integrator (soma/cell body)?
modify upstream inputs
Synapse distance?
synapse represents a high resistance for electrical transmission - need chemical NT
20-100nm
What is the action potential?
wave of depolarisation that causes depolarisation of nerve terminal to trigger NT release
What are the 3 types of NT?
amino acids (glutamate - major excitatory, GABA - major inhibitory, glycine)
amines (noradrenaline, dopamine, ACh)
neuropeptides (opioid peptides)
mediate rapid (micros-ms) or slower (ms)
What does transmitter release require?
increase in intracellular Ca (100microM)
transmission restricted to specialised structure (asymmetric synapse - lots of presynaptic NT vesicles)
How can rapid release of NT occur?
vesicular proteins /presynaptic membrane proteins
- synaptic vesicles are filled with NT are PRIMED
- a helical tails of proteins overlap to form supercoils which are active - interaction between vesicles and synaptic membrane proteins allows rapid response - complex docked in synaptic zone
- Ca channels are close to primed vesicles - Ca sensor in protein complex is activated by Ca entry and causes conformational change in complex
- Promotes fusion with membrane and opening of pore to release NT - EXOCYTOSIS
What targets vesicular proteins?
neurotoxins
tetanus toxin - target vesicular proteins, paralysis
botulinum toxin - target vesicular and membrane proteins, flaccid paralysis
alpha latrotoxin - deplete NT release by stimulating exocytosis
What are tetanus and botulinum toxins?
Zn dependent endopeptidases that inhibit transmitter release
What 3 things does transmitter release require?
- vesicles to be docked on presynaptic membrane
- protein complex formation to enable rapid response to Ca entry
- ATP and vesicle recycling
What is special about synaptotagmin?
Ca sensor
part of it is embedded in vesicle to allow NT sensitivity and release
What defines neurotransmitter action?
post synaptic receptor kinetics 1 - ION CHANNEL RECEPTOR fast (micro to msecs) all excitatory/inhibitory transmission (Na+)
2 - G PROTEIN COUPLED RECEPTOR
slow (s/min)
effectors may be enzymes -a adenyl cyclase, PLS, cGMP-PDE) or channels (Ca/K)
Examples of ion channel receptors?
CNS
glutamate - Na, depolarisation of membrane
GABA/Gly - Cl-, hyperpolarised
NMJ
ACh at nicotinic receptors
Examples of G protein coupled receptors?
CNS and PNS:
ACh at muscarinic receptors dopamine noradrenaline 5HT neuropeptides (encephalin)
Where is glutamate and GABA typically found?
glutamate - dendritic spines
causes increase in membrane potential
GABA - soma (can inhibit as it is downstream)
hyperpolarises potential - more negative (greater distance to threshold)
What are the different glutamate receptors?
ALL 4 SUBUNITS
AMPA receptor (Na) - most fast excitatory synapses
NMDA receptor (Na and Ca) - only operates on already depolarised cell
slow component of excitatory transmission for coincidence/learning mechanisms
What is the effect of Ca on AMPA receptor?
modifies the receptor to potentiate its response (depolarisation of post synaptic membrane)
activates protein synthesis that modifies synapse formation
Describe reuptake of NT glutamate from synapse?
use excitatory amino acid transporter (EAAT) that is abundant in glial cells
- take glutamate to glial cell
- metabolised using glutamine synthetase to form glutamine
OR
EAAT also on nerve terminal
- use glutamate to refill synaptic vesicles
What is associated with excess glutamate in the synapse?
abnormal cell firing leading to seizures (epilepsy)
as glutamate [] decreases, glutamine increases
What is epilepsy?
affects 50 million worldwide - most common neurological condition, 30% refractory by treatment
characterised by recurrent seizures due to abnormal neuronal excitability
What is the difference in structure between glutamate and GABA?
GABA lacks COOH group which would form glutamate
What enzyme converts glutamate to GABA?
glutamic acid decarboxylase
(GAD) - (B6)
highly concentrated in nerve terminals and GABA neurones
What does GABA do to cell firing?
increases threshold to cause a depolarisation
INHIBITORY NT
What is the GABA receptor?
GABAaR
What transporter involved in the transport of GABA from synaptic cleft?
GABA transporter (GAT) on glial cell/post synaptic membrane
What enzyme metabolises GABA to succinate semialdehyde?
GABA transaminase (GABA-T) in glial cell
succinate to TCA cycle
Describe the structure of GABA receptor?
5 subunits - pentameric
drugs that modulate activity of GABA receptor to enhance GABA transmission (antiepileptic, sedative, muscle relaxant, anti-anxiety )
- facilitate GABA transmission by enhancing ongoing hyperpolarisation
How do drugs that facilitate GABA transmission work?
Cl- channel opens after GABA binds
Cl- channel modified at allosteric sites
What is benzodiazepine?
acts on site of complex to affect frequency of channel opening when activated by GABA
enhances ongoing inhibition by GABA
What are barbiturates?
act on different site of GABA receptor
increase open time of reponse
Epilepsy treatment?
dampen down excitatory activity by facilitating inhibitory transmission
drugs target GABA synapse
