neurotransmitters Flashcards
what is neurotransmission
information transfer across a synapse
requires neurotransmitters and their interaction with postsynaptic membranes
abnormalities in this cause psychiatric and neurological disorders including Parkinson’s, epilepsy and schizophrenia
40% genome involved
Features of neurotransmission
rapid diversity - many genes involved adaptability plasticity learning and memory
describe membrane plasticity
changes in the responses
modified by the nature of the response and structural changes in the number of synapses
describe adaptability of neurotransmission
dynamic and changing all the time
change in input to cells and pathways by environmental stimuli
what makes neurotransmission diverse
the receptor on the second cell
describe the 3 stags of synaptic transmission
- biosynthesis, packaging and release of NT
- synaptic activation of the second cell - receptor cation
- signal integration and conduction by the second cell - integration of all inputs
how does the structure of the neuron relate to neurotransmission
spines on the dendrites receive information - information reception
soma - integration and regulation of other inputs
axon - electrical part, rapid transfer of the action potential
nerve endings and terminals - synapses to downstream cell
what is the time frame of chemical transmission
for the AP to go from the 1st to 2nd cell it takes 2ms
events between this take fractions of ms
features of the synapse
presynaptic terminal/nerve ending
gap 20-100nm - enough to be resistance to electrical signals so chemical signal needed
postsynaptic region with receptors - receptive area either dendrite or cell soma
mitochondria
synaptic vesicle - with NT. some electron dense with NT, others less so
post-synaptic density - the high number of proteins in signalling pathway and those that regulate activity of the downstream cell
what does T stand for in a synaptic vesicle
typical NT
describe neurotransmission
diverse
may mediate rapid us-ms (thought) or slower effects ms
vary in abundance from mM to nM in CNS
neurons receive many inputs which are integrated to produce a single effect
Types of neurotransmitter
Amino Acid
amines
neuropeptides
amino acid neurotransmitters
glutamate - excitatory - intermediary metabolism, TCA cycle, transfer of amino groups in many pathways, most potent AA - only need small quantities (10 to the -15mol), most abundant
gamma amino butyric acid - as important as glutamate, inhibitory
glycine - in brain stem and spinal chord, less common present in mmol concentration
what are the amine NT
acetyl choline
noradrenaline
dopamine
neuropeptide NT
opioid peptides
order of abundance of NT from high to low
AA
amine
neuropeptides
describe the sequence of events in the activation of the synapse
Na enters the presynaptic neuron because of depolarisation
outflow of potassium
calcium entry - through calcium channel
NT release into synapse
NT bind to receptor - allow Na into postsynaptic nuron through ion channel - depolarisation
NT enter presynaptic neuron - removed to stop action potential at postsynaptic neuron
K enter pre-synaptic neuron by ATP transporter
Na leave pre-synaptic neuron using ATP
replenish vesicles for next AP
essential components of synaptic transmission
restricted to the synapse fast - 200us calcium increase to 200um locally synaptic vesicles containing 4000-100000 molecules each vesicles close proximity to membrane some fuse and release NT
what is the relationship between Ca and NT release
electrical - biophysical event
electromechanical transduction
200us
how does rapid release of NT occur
proteins on vesicle membrane and neuron membrane
vesicles filled with NT docked
the a-helix of the proteins overlap - vesicles stay associated in active zone, relatively stable
Ca entry activates a ca sensor (synapototagmin) in the protein complex - conformational change - promote fusion of membrane and opening of pore. Calcium sensitive complex response
exocytosis
neurotoxin targets
tetanus - target vesicular proteins - paralysis - block NT release
botulinum toxin - vesicular and membrane proteins - placid paralysis - block NT release
Latrotoxin - prevent exocytosis and resealing of the membrane
What is required for NT release
vesicles docked to presynaptic membrane
protein complex formation between vesicle, membrane and cytoplasmic regions - allow docking and rapid response to Ca entry
ATP and vesicle recycling
ion channel receptors
fast - us-ms
mediate all fast excitatory and inhibitory transmission
transmitter bind
conformational change eg with synapototagmin
diversity and rapid information flow
many subunit conformations
G-protein coupled receptor
slow - s/mins
transduce response to recptor and effector
effectos can be enzymes eg adenyl cyclase - cAMP - PK - activate key protein, phospholipase C, cGMP-PDE
or channels ca/k
Glutamate receptor
GLUR
dendritic spines
excitation
open Na channel - polarise
GABA receptor
GABAR chloride entry -ve charge hyperpolarised raise threshold for response inhibitory typically on soma
GlyR
similar to GABAR
higher cl conductance
effect of receptors on membrane potential
increase in membrane potential - glutamate
negative membrane potential - GABA
describe the different types of glutamate receptors
classical - AMPA receptors, fast excitatory synapses, rapid onset offset and desensitisation - cause depolarisation
NMDA - slow component, serve as coincidence detectors underly learning mechanisms (events happen after each other and change the response Ca activated phosphorylation receptor - alter transcription - make new synapse and protein, understand the learning process, only operate when cell is already depolarised, calcium enters with Na, Ca modifies AMPA - potentiating the response - activating protein synthesis which modifies synapse formation
what happens at an excitatory synapse
mediated my glutamate
linked to intermediary metabolism a-ketoglutarate is in the vesicles glutamate transporter (GLUR) on post-synaptic membrane excitatory amino acid transporter (EAAT) has high capacity to take glutamate up into the glial cell, EAAT abundant in glial and neuron cells in glial cells glutamate -- glutamine catalysed by glutamine synthetase. in nerve cell the glutamine returns to the vesicles
what does AMPA receptors stand for
alpha amino-3-hydroxy-5methyl-4-isoxole- propanoic acid
what does NMDA stand for
N-methyl-D aspartate
what happens if there is extra glutamate in the synapse
seizures
electrical activity increases
glutamate converted to glutamine
what happens at an inhibitory CNS synapse
mediated by GABA which has a similar structure to glutamate
intermediary metabolism - glutamate
glutamate — GABA catalysed by glutamate acid decarboxylase (GAD [B6])
on post synaptic membrane - GABAaR (GABA receptors)
hyperpolarise membrane, threshold increases
GABA transporter (GAT) - GABA into glial cells
GABA - succinate semialdehyde catalysed by GABA transaminase (GABA-T) which goes into TCA cycle
in nerve cell GABA is returned to vesicles
describe the pentameric organisation of the GABA receptor and binding domains
on the receptor the binding channels are: steroids, benzodiazepines, Zn, convulsant, ethanol, barbiturates
describe the action of drugs on GABAaR
the drugs modulate the activity of the receptor
modify GABA activated chloride response - opening of the channel is modified at allosteric sites
benzodiazepines - important inhibitory action
antiepileptic, anxiolytic, sedative, muscle relaxant - all enhance GABA transmission - important for treatment of epilepsy
what is epilepsy treatment’s focus
dampens excitatory activity
facilitate inhibitory transmission
target the GABA synapse
why is chemical transmission used at a synapse rather than electrical
transferred in a concise space - electrical signal would need a larger SA
