Neurochemistry 1 Flashcards
Name the different types of glial cells
Which are the most abundant
- Astrocytes
- Oligodendrocytes
- Schwann cells
- Microglia
Astrocytes are the most abundant
Function of microglia
Immune cells
Secrete cytokines - when they become activated this increased inflammatory cytokines and cause inflammation
this is seen a lot of people with neuro degenerative diseases
Define synapse
Specialised sites where neurons communicate with other cells via NTs
Name the 4 steps in neurotransmission
- NT synthesised and stored in high conc in nerve terminals, in synaptic vesicles
- Released upon stimulation of nerves
- Stimulates target organs/cells
- Active mechanisms to terminate its effect
Name the 3 classifications of NTs
GIve examples
Classical (small molecule) NTs
Neuropeptides (non-classical NTs) - short peptides (3-36 AAs long) that are neuroactive
Unconventional - NO (cannot be stored in nerve terminal), CO (cannot be stored in nerve terminal), arachidonic acid (not easily stored in nerve terminal)
Name the 3 small molecule NTs that are derived from tyrosine
Dopamine
Norepinephrine
Epinephrine
As a general rule, what do classical NTs have in common
Either AAs or derived from AAs (except ACh)
What is serotonin derived from
What is its synonym
Tryptophan
5-hydroxytryptamine
What is histamine derived from
Histidine
What is GABA derived from
Name its synonym
What is unique about GABA
Derived from glutamate
γ-aminobutyric acid
Non-typical but still has an amino grp and a carboxylic acid grp
What do ACh, glycine and glutamate have in common
All classical (small molecule) NTs
In step 1 of neurotransmission, synthesis and storage of NT in high conc in nerve terminals, where does the synthesis usually occur
Cytosol
How is NT transported into synaptic vesicles
Dependent on 2 proteins:
- H+-ATPase (proton) pump - creates H+ gradient (by pumping H+ INTO vesicle) across vesicle membrane, pumping
- H+/NT antiporter - uses the energy stored in this H+ gradient so H+ leaves and a NT enters
What is step 2 in neurotransmission
Release of NT upon stimulation of the neuron
How is NT released
Exocytosis of synaptic vesicles is tightly coupled to arrival of an AP at the axon terminus
Also dependent on Ca2+ influx into the presynaptic nerve terminal
Define AP
What is its speed
Electrical signal that travels from neuronal cell body down the axon to the axon terminus
Characterised by high speed (up to 120 m/s) with no loss of signal over long distances
What structures wrap around the axon
Oligodendrocytes/Schwann cells
What is the composition of myelin
70-80% lipid
20-30% protein
Role of Ca2+ in NT release
This electrical signal must be converted into a chemical signal - Ca2+
As a result of the opening of the VG Ca2+ channels, how does [Ca2+] change
80-100 nM → 1-100 uM
Increase in Ca2+ is highly localised
How is a low Ca2+ conc maintained in the axon
Ca2+ pumps pump Ca2+ back out to maintain low conc in cytosol
Mitochondria also have a Ca2+ uptake system
Name 2 SNARE proteins
SNAP25 and Synaptobrevin
Function of Synaptotagmin
Ca2+ sensing
Function of Synapsin
Links proteins to cytoskeleton and keeps vesicles in place
What does the V-ATPase do
Pumps H+ into cell
Name the SNARE protein present on the VESICULAR membrane
Synaptobrevin
Name the SNARE protein present on the plasma membrane
Syntaxin
Name the SNARE protein present on both membranes
SNAP-25
Function of SNARE proteins
Control fusion of 2 membranes
Describe the structure of synaptotagmin
Made up of long alpha helices - bind and become intertwined with each other - stable complex, that is highly resistant to degradation
What does the SNARE complex look like
MOA of action of synaptotagmin
Affinity for Ca2+ = 1uM
Binding of Ca2+ to synaptotagmin changes its confirmation and it pulls the vesicle closer to the mebrane
this then stimulates the fusion of the 2 membranes and NT is exocytosed into the synaptic cleft
What diseases affect the presynaptic terminal - give an example
What are the symptoms
What is it caused by
Some myasthenic syndromes e.g. the autoimmune disease Lambert-Eaton myasthenic syndrome (LEMS) - attacks presynaptic Ca2+ channels
Present as muscle weakenss that worsens with exertion
Caused by abnormal transmission at neuromuscular synapses
ALSO clostridium bacterial toxins (even if you stimulate this neuron it cannot change the voltage)
Describe the vesicle cycle
Loaded with NT
Move into reserve pool
Linked via synapsin to cytoskeleton
AP arrives they become mobilised to nerve terminal pre-synaptic membrane
Docked onto membrane and primed
Linkages to membrane are shown
Ca2+ influxes into cell and then get fusion with the plasma membrane and exocytosis of its contents
The membrane that was part of the vesicle gets re-taken up - clatherin coating
Empty vesicle then gets reloaded with NT
Where does botulinum toxin come from
Describe its structure
From clostridium botulinum, which causes food poisoning and paralysis
Heavy chain involved in entry into neurons in NMJ
Light chain has protease activity
Why does BOTOX have an effect on muscles
Attracted to neurons at the neuromuscular junction
Distinguish between the heavy and light chain in botulinum toxin
Heavy chain - involved in entry into neurons in the NMJ
Light chain - protease activity
How can toxins affect transmitter release
Because the light chain has protease activity, it degrades the snare proteins and the snare complex cannot form => vesicle will not be able to fuse with the plasma membrane and there will be no NT release
Nerve terminals can grow new ones but takes months
Medical uses of Botox
Strabismus (crossed eyes)
Blepharospasm (uncontrolled blinking)
Hyperhidrosis (excessive sweating)
Glabellar frown lines
Chronic migraines
What is step 3 in neurotransmission
When it is released into the synaptic cleft, the NT binds and activates receptors on the post-synaptic cell membrane
Name the 2 types of NT receptors
Ionotropic - ligand gated ion channel
Metapotropic - GPCR
What receptors do classical NTs bind to
Both to specific ionotropic and metabotropic receptors
What is the defining feature of ionotropic receptors
Generally heteromeric - individual receptors are made of multiple subunits
Name the glutamate receptors
Overview of subunits for the different types of receptors
MOA of heteromeric ion channels
NT are binding to 1 or 2 of these subunits - we notice that certain subunits have a higher affinity of binding than others
Change the conformation and opens channel in the interior pore formed by the 5 subunits
This allows flux of certain ions
Signal is transduced into post-synaptic cell
Describe metabotropic receptors
Give examples
What sort of response do they elicit
7 transmembrane domain
e.g. Adenylate cyclase, phospholipase C or A, ion channels
Responses tend to be slower than for ionotropic receptors and of longer duration
What are the different receptor classes and their receptor subtypes
Step 4 in neurotransmission
Termination of the effect of the NT
Name the main mechanisms for termination response
- Enzymatic degradation
- Uptake into 1) neuron via specific membrane transport protein, then uptake into synaptic vesicles, 2) surrounding astrocytes
- Diffusion away from synaptic cleft
