l6 Flashcards
what are the vesicles above the active zone anchored to the cytoskeleton by?`
Synapsin
what do ca2+ activate in the presynaptic button
CaMKII
what does CaMKII do
it phosphorylates synapsin, so p-synapsin can no longer bind to the cytoskeleton, allowing individual vesicles to dock onto the active zone
what complex docks the individual vesicles to the plasma membrane in the active zone
SNARE complex
At docking: what are the types of proteins
Synaptobrevin and synaptotagmin bound to the vesicle
Syntaxin and SNAP-25 at the membrane
They (except synaptotagmin) combine to FOrm SNARE complexes
What is the function of snare complexes
They pull the membranes together
what proteins do the calcium ions bind to at docking stage
Synaptotagmin
What does CA2+ bound synaptotagmin catalyse-
membrane fusion by binding to SNARE’s & plasma membrane
what is priming
Invoes partial assembly of SNARE complexes so docked vesicles are ready for fusion (to respond to ca2+)
what process re-forms the vesicles
Endocytosis recovers them, from the CSM
what do clostridal toxins do
cleave SNARE proteins
what does the Botulinum toxin do
Decreases neuromuscular transmission of ACH
acts directly at the neuromuscular junction. The muscles lose all input and so become permanently relaxed (treatment of muscle spasms).
what does Tetanus toxin do
inhibits the release of Glycine and GABA at inhibitory neurons, resulting in dis-inhibition of cholinergic neurons, which causes permanent muscle contraction.
Botox and tetanus both affect…
SNARE proteins
what does LEMS attack
Presynaptic CA2+ channels
what do cognitive disorders impair
Transynaptic signalling
Describe the action of Vesicular transporters powered by proton gradient
(can happen for all membrane transporters not just Glutamate and GABA-slide 14)
ATPase proton pump loads up vesicles with H+
making vesicles acidic
Plasma membrane transporters powered by electrochemical gradient
[Na+] higher outside / [K+] higher inside
Glutamate co-transported with 2 Na+
. 1 glutamate traded for 1 H+ (counter-transport mechanism
what function do glial cells have at the synapse when activated by neurotransmitter
They experience an increase in intracellular ca2+ and release tranmmitters of their own into the synapse to enhance or inhibit synaptic activity
what are the 4 main types of neurotransmitters
AA
monoamines
ACH
Neuropeptides
What are 3 key features that distinguish ACH and AA and amines from Neuropeptides
The first 3 are:Synthesized locally in presynaptic terminal
Stored in synaptic vesicles
Released in response to local increase in Ca2+
3 key features of neuropeptides
Synthesized in the cell soma and transported to the terminal
Stored in secretory granules
Released in response to global increase in Ca2+
give an example of a fat and slow neurotransmitter
Fast: AA
slow:neuropeptide
What is the theory behind why some neurotransmitters are fast and why others are slow
Fast transmitters (e.g. Glu) are stored in synaptic vesicles that are docked close to voltage-gated calcium channels in the membrane of the nerve terminal, and are released in a short burst when the membrane is depolarised. Slow transmitters (e.g. neuropeptides) are stored in separate vesicles further from the membrane. Release is slower, because they must first migrate to the membrane, and occurs only when [Ca2+] builds up sufficiently
give example s of AA transmitters that are excitatory and inhibitory
Excitatory : Glutamate (CNS)
Inhibitory: GABA (Brain)
Glycine (Spinal cord and brainstem)
what is the function of the serotonergic system
Function is: Mood Sleep Pain Emotion Appetite
what is the meaning behind-“ why have more Neurotransmitters”
What do all the other neurotransmitters do? In general, they have modulating effects rather than information-transmitting effects. That is, the release of neurotransmitters (other than GABA or Glu) tends to activate or inhibit entire circuits of neurons that are involved in particular brain functions. For example, secretion of Ach activates the cerebral cortex and facilitates learning, but the information that is learned and remembered is transmitted by neurons that secrete Glu and GABA.
what are the types of neurons
slide 22
: (A) pyramidal, (B) spiny stellate, (C) bi-tufted, (D) double bouquet, (E) small basket, (F) large basket, (G) chandelier
where are the 2 sources of glutamate
1) from glucose via the Krebs cycle
2) from glutamine converted by
glutaminase into Glutamate
what is glutamate loaded by and stored by
vesicular glutamate transporters (VGLUTs)
what is glutamate reuptaken by
excitatory amino acid transporters (EAATs) in glial cells
Glial cells convert
GLU-glutaminase into glutamine
what is GABA synthesized from and by what
Glutamate
catalysed by GAD-Glutamic acid decarboxylases
what transpoter loads both GABA and glycine into the vesicles
vesicular GABA transporter,
Describe events of cerebral ischaemia
the metabolic events that retain the electrochemical gradient are abolished
reversal of the Na+ / K+ gradient
transporters release glutamate from cells by reverse operation
excitotoxic cell death (Ca2+ -> enzymes -> digestion)
Describe how the rape drug GHB works
a GABA metabolite that can be converted back to GABA
Increases amount of available GABA
too much leads to unconsciousness and coma
give 2 diff categories of monoamines
Catecholamines
Indolamines
Name some catecholamines
Dopamine
Epinephrine
Norepinephrine
Name an indolamine
Serotonin
Look at slide 29 for dopamine synthesis
LOOK AT IT
How is catecholamine stored and by what
Into vesicles by VMAts
similar to the AA
How does L-Dopa provide modulation of catecholamines and what is it used to treat
L-DOPA, Levodopa, the precursor of dopamine, is used as a treatment for Parkinson’s disease . Dopa decarboxylase converts it into dopamine increasing the pool of releasable transmitter.
Describe the process of how Catecholamines are re-uptaken
reuptake into the axon terminal by transporters powered by electrochemical gradient (Dopamine transporters (DATs), Norepinephine transporters (NETs) etc.)
in the cytoplasm the catecholamines are:
- reloaded back into vesicles
- enzymatically degraded by Monoamine oxidases (MAOs)
or
- inactivated by Catechol-O-methyl-transferase (COMT)
Describe 2 other modulators of dopamine
Amphetamine reverses transporter so pumps out transmitter and blocks
reuptake (DA & NE)
Cocaine and Methylphenidate (Ritalin) block DA reuptake into terminals. More DA in synaptic cleft – extended action on postsynaptic neuron.
LOOK AT SLIDE 33
LOOK AT IT
How I serotonin stored and re-uptaken
stored in vesicles
signal terminated by reuptake by Serotonin transporters (SERTs) on presynaptic membrane
- destroyed by MAOs in the cytoplasm
Give 2 drugs that modulate Serotonin uptake and reuptake
Fluoxetine (Prozac) blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) (treatment of depression, OCD)
Fenfluramine stimulates the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity
how is ACH made
Choline acetyltransferase (ChAT, CAT) converts choline+ Acetyl CoA (coenzyme A) into acetylcholine
what packages ACH into vesicles
is packaged into vesicles by
vesicular acetylcholine transporter (VAChT).
what happens to choline during reuptake and is it a rate limiting step
Choline is transported back into the
presynaptic terminal and converted to
acetylcholine
- amount of choline is rate limiting step
Give an example of a drug modulating ACH
Neostigmine-
block the breakdown of ACh, prolonging its actions in the synaptic cleft
what are the differences between the neuropeptide vesicles
The neuropeptides have large dense-core vesicles compared to the small clear-core vesicles of the other neurotransmitters
differences in the site of neuropeptide synthesis and other neurotransmitters
Neuropeptides: Synthesis and packages of neurotransmitters at synaptic button aswell as transport of precursors into the terminal.
In Peptide transmitters: Both enzymes and precursors are packaged into the vesicles from the enzymes
How are neuropeptides released and degraded
Follow the secretory pathway and NOT released in the same manner as small molecule transmitters
dense core vesicle fusion and exocytosis occurs as a result of global elevations of Ca2+
neuropeptide vesicle membrane recycled but not refilled
bind to and activate receptor
neuropeptides signalling is terminated by diffusion from site of release and degradation by proteases in the extracellular environment
release is slower than small molecule release and signals may be maintained for longer
Retrograde signalling: give examples of some
NO and CO
How does NO signalling work
Nitric oxide made in postsynaptic neuron by Nitric oxide synthase
(activated by the binding of Ca2+ and calmodulin)
2) The gas is not stored but rapidly diffuses from its site of synthesis. Diffuses between cells (into presynaptic cell - retrograde transmitter)
Activates guanylyl cyclase which makes the second messenger cGMP
4) Within a few seconds of being produced NO is converted to biologically inactive compound (switching off the signal)
5) Potentially useful for coordinating activities of multiple cells in a small region (tens of micrometers) (how big is a neuron?)
How does Endocannabinoids works
Small lipids which mostly cause reduced GABA release at certain inhibitory terminals.
