Neurotransmission Flashcards
Describe chemical transmission
Chemical transmission: neurotransmitters in vesicles
- Small clear vesicle –> glutamate,
GABA, acetylcholine, glycine - - Small vesicle with dense core –>
catecholamine’s
- Large vesicle with dense core –>
neuropeptides
Describe electrical transmission
Electrical transmission: electrical gradient based on ion movements
- Need to reach threshold for propagation of action potential
- Lowest threshold is @ the initial segment, just caudal to the axon hillock
Describe excitatory post synaptic potential (EPSP).
Excitatory post synaptic potential (EPSP)
- Depolarization response
- Opening of Na+ or Ca2+ channels in post synaptic neuron (influx)
- Summation of depolarization eventually reach threshold potential
- Action potential will then be propagated
- Slow EPSP = ↓ conductance of K+
Describe Inhibitory post synaptic potential (IPSP).
Inhibitory post synaptic potential (IPSP)
- Hyperpolarization response
- Opening of Cl- channels in post synaptic neuron (influx) –> membrane potential now more (-)
- Slow IPSP = ↑ conductance of K+
What’s the difference between direct and indirect inhibition?
Direct inhibition - ex. Post synaptic inhibition of IPSP
- Not a direct consequence of a previous
post synaptic neuron
Indirect inhibition
- Due to effect of previous post synaptic
neuron discharge
○ Ex. Refractory period
○ Hyperpolarization
Ex. Repeated firing in spinal cord
What’s the difference between pre- and post- synaptic inhibition?
Pre synaptic inhibition
- Neuron acts on another excitatory neuron to ↓ excitatory neurotransmitter release (axoaxonal synapse_
Post synaptic inhibition
- Inhibitory neurotransmitters from an inhibitory neuron acts directly on the post synaptic neuron
Describe how action potential is generated at the neuromuscular junction.
Neuromuscular junction
- Axon of motor neuron ends @ motor end plate of muscle
- Action potential carried by the motor nerve
- Ca2+ influx
- Exocytosis of acetylcholine in synaptic vesicles
- Acetylcholine binds to receptors on the motor end plate
- Na+ influx, K+ efflux –> depolarization
- Action potential generated –> propagated in both direction along the sarcolemma
- Muscle contraction occurs
Describe how glutamate, gaba, acetylcholine, seretonin, and catecholamines are made. ***
Describe the action of glutamate as a neurotransmitter
Glutamate = main excitatory transmitter in CNS
- Produced in Krebs’ cycle via GABA transaminase, or
- In glial via glutamine synthetase
3 main receptors:
1. AMPA
2. Kainate
3. NMDA
NMDA - opens when glutamate binds to it
Needs less Mg (depolarization) by activation of AMPA and kainite receptors
NMDA receptor agonist can be used to treat chronic pain
How is glutamate secreted?
Glutamate Secretion
- Produced in mitochondria via Kerbs’ cycle from glutamine
- Concentrated into vesicles by vesicular glutamate transporter
- Exocytosis out –> G-coupled or ionotropic receptors on post synaptic membrane
- Reuptake facilitated by Na+ dependent glutamate transporters
- Can go into glia cell, converted to glutamine via glutamine synthetase, diffuse back to nerve, and hydrolyzed back to glutamate
How is glutamate secreted?
Glutamate Secretion
- Produced in mitochondria via Kerbs’ cycle from glutamine
- Concentrated into vesicles by vesicular glutamate transporter
- Exocytosis out –> G-coupled or ionotropic receptors on post synaptic membrane
- Reuptake facilitated by Na+ dependent glutamate transporters
- Can go into glia cell, converted to glutamine via glutamine synthetase, diffuse back to nerve, and hydrolyzed back to glutamate
What’s the function and main receptors for GABA?
GABA = main inhibitory neurotransmitter
- Formed by decarboxylation of glutamate via glutamate decarboxylase (GAD)
- Transported into vesicles by vesicular GABA transporter (VGAT) –> does both GABA and glycine
Receptors:
- GABA a & GABA b = widely distributed in CNS
- GABA c = almost exclusively in retina of adult vertebrates
- GABA a & GABA c = ionotropic receptors –> Cl- entry
- GABA b = G coupled-protein receptor –> influences Na+/Ca2+ influx
- GABA a –> beznodiazapam ↑Cl-conductance
○ Barbiturates will enhance it’s inhibitory effect , also suppress AMPA receptor-mediated excitation
○ Low level of activation all the time - to cut down noise from the other ones
What’s the action of glycine as a nuerotransmitter?
Glycine = both inhibitory and excitatory
- ↑sensitivity to glutamate if bound to NMDA receptor
- Also ↑Cl- conductance
- Cl- channel = glycine receptor for inhibitory effects
Described norepinephrine secretion.
Monoamine Secretion (norepinephrine)
- Production in the cytoplasm & secretory granules
- Concentration maintained by VMAT (vesicular monoamine transporter)
- Released into the synaptic cleft via exocytosis
- Many receptors on the postsynaptic membrane (G-protein coupled receptors)
- NET = norepinephrine transporter –> involved with reuptake
Generally not a mediator @ post synaptic endings
Described acetylcholine secretion.
- Acetylcholine transported into vesicle via vesicle-associated transporter (VAT) –> peptide P and ATP also comes in
- Exocytosis of vesicle requires opening of voltage-sensitive Ca2+ channels
○ Requires synaptosome-associated membrane proteins (SNAPs) and vesicle-associated membrane proteins (VAMPs) - Acetylcholine is metabolized by acetylcholinesterase on the post synaptic membrane
- Modulation of acetylcholine release done via hetero receptors and acetylcholine autorecepto
What are the receptors for acetyhlcholine?
Muscarinic cholinergic
- Stimulating actions on smooth
muscles
- Coupled G-protein receptors
Nicotinic cholinergic
- Simulating actions on skeletal muscles and sympathetic ganglia
- Ion-gated –> allows Na+ entry when activated
- Neural ones also has high permeability for Ca2+
Where are acetylcholine found?
- Neuromuscular junction, autonomic ganglia, postganglionic parasympathetic nerve target organ junction, some postganglionic sympathetic nerve-target junctions
- Secreted by all nerves that exit the CNS
- Made in nerve terminal from choline and acetyl-CoA by choline acetyltransferase (ChaT)
- Choline transported from extracellular fluids via choline transporter (CHT) –> needs Na+
What are the dopamine receptors?
Dopamine
- Active reuptake post secretion into synaptic cleft via Na+ and Cl- dependent dopamine transporter
- Metabolized to inactive compound by MAO and COMT
Receptors
- D1 like (D1 and D2) or D2 like (D2, D3, and D4)
- All are metabotropic G-protein couple receptors
- Activation of D1 like ↑ cAMP; opposite for D2 like
Describe serotonin
- Aka 5-HT
- Made from tryptophan
- Tryptophan –> tryptophan hydroxylase –> 5-hydroxytryptophan –> aormatic L-amino acid decarboxylase –> 5HT
- Transported into vesicle via VMAT
It’s in chemoreceptor trigger zone! Used to treat nausea (ondansetron)
What are the serotonin receptors? ***
- 7 classes of 5-HT receptors; only 5-HT3 is not G-protein coupled receptor
- 5-HT2a: mediates platelet aggregation and smooth muscle contraction
- 5-HT2c: KO mice don’t respond to leptin (eat lots) and have fatal seizures
- 5-HT3: GI, area postrema –> associated with vomiting
- 5-HT4 : also in GI –> peristalsis, facilitate secretion. Also in brain
- 5-HT6 & 5-HT7: also in brain –> 5-HT6 have high infinity for anti-depressants
How is serotonin secreted?
- Exocytosis after activation of voltage gated Ca2+ channel
- Transported back via 5-HT transporter (serotonin transporter, SERT)
- Auto receptor 5HT1D modulates 5-HT release
- Reuptake ones are either sequestered in vesicle, or converted to 5-hydroxyindole acetaldehyde by mitochondrial monoamine oxidase
What are enkephalins?
They are opioid peptides
- receptors that bind morphine are found in the brain and GI
- Enkephalins = endogenous ligand –> metenkephalin and leu-enkephalin
- They bind to opioid receptors, so are called opioid peptides
- Enkephalins
○ Nerve endings in GI tract and
many parts of brain
- Synaptic transmitter
- Also ↓ GI motility
What are the 3 classes of opioid receptors?
- µ, ĸ, δ
- All are G-protein coupled receptors
- Inhibit adenylyl cyclase
- µ: ↑K+ conductance –> hyperpolarization
- ĸ & δ: closes Ca2+ channels
What is substance P?
- Polypeptide with 11aa residue
- Found in intestine, peripheral nerves, many parts of CNS
- Other members of the family (Tachykinin) include neurokinin A and neurokinin B
- Found in high concentration of primary afferent neurons in the spinal cord
- 1st connection in the pain pathway
- Involved in peristalsis in GI
- 1st connection in the pain pathway
What are the 3 receptors for substance P?
- NK1-3
- All are metabotropic G-protein coupled receptors
- NK1 likes substance P (in CNS) –> IP3 and DAG
- Receptor antagonist (maropitant) can be used for nausea
What is nitric oxide (NO)?
- Release by endothelium, and brain as well
- Activates guanylyl cyclase (gas!) diffuses through membrane
- Not stored in vesicles –> produced on demand
- Synthesis can be activated by NMDA –> Ca2+ influx, activation of neuronal nitric oxide synthase
- Could enhance release of glutamate
What are the actions of endogenous cannabinoids?
- 2-arachidonyl glycerol
- Anandamide
- Also not stored in vesicles
- Synthesized in response to Ca2+
- Act on CB1 receptor
○ G-protein mediated ↓extracellular
cAMP
○ Common in central pain pathway
○ Agonists have anti-nociceptive
effect - Retrograde synaptic messengers
- CB2 receptors may be targeted for chronic pain therapy (doesn’t induce euphoria like CB1)
How are catecholamine forms?
- Norepinephrine, epinephrine, dopamine
- Formed via tyrosine, which can be formed from phenlalanine - though they are mostly dietary origin
- Tyrosine is transported in via Na+ dependent channel
- Tyrosine –> Tyrosine hydroxtlase (TH) –> dopa –> dopa decarboxylase –> dopamine
- Transported into vesicle via VMAT
- Once inside vesicle, dopamine is converted to norepinephrine by dopamine β-hydroxylase
○ Only small molecule transmitter
that’s produced in vesicle rather
than transported in! - Can measure concentration in urine –> ex. For pheochromocytoma, not the best test, but can be done
Which receptors do the catecholamines act on?
- Epinephrine and norepinephrine both act on α & β adrenoceptors
○ Norep likes α, epi likes β
○ Metabotropic G-protein coupled
receptors
What’s the function of α-1 adrenergic receptors?***
Most α-1 adrenergic receptors lead to activation of IP3 and DAG –> ↑ intracellular Ca2+ release and activate protein kinase C
○ Excitatory
○ Smooth muscle and heart
What’s the function of α-2 adrenergic receptors?***
- Most α-2 adrenergic receptors activate G I inhibitory proteins to inhibit adenylyl cyclase and ↓cAMP
- Other α-2 adrenergic receptors also lead to K+ influx –> hyperpolarization, and inhibit neuronal Ca2+ channels
○ Inhibitory
○ CNS, pancreatic islets cells, nerve
terminals
What are the functions of β-adrenergic receptors?***
- β-adrenergic receptors activate stimulatory Gs protein to activate adenylyl cyclase to ↑cAMP
○ β-1 @ heart and renal
juxtaglomerular cells
○ β-2 @ bornchial smooth muscle
and skeletal muscle
○ β-3 @ adipose tissue
What are the function of the histamine receptors?
- H1, H2, H3
- H3
○ Pre-synaptic, mediate inhibition of
the release of histamine and
others via G-protein - H1
○ Activate phospholipase C - H2
○ ↑intracellular cAMP - H4
May regulate the immune system
