NT systems and pathways Flashcards
Receptor antagonists
Inhibitors (block the normal activity of a NT), binds the receptor and blocks its activity by preventing it other molecules from binding
Receptor agonist
Binds to receptor, mimicking the activity of its normal ligand
What receptor does nicotine bind to?
Nicotinic acetylcholine receptor (receptors often named after agonists)
Example of how one NT can act on multiple receptors - glutamate
Glutamate can affect AMPA (lets in Na+ and K+), NMDA (lets in Na+, K+, and Ca2+), and kainate receptors (lets in Na+ and K+)
Phosphorylation
- Add phosphate (PO4) to protein
- Carried out by protein kinases
Dephosphorylation
- Remove phosphate (PO4) from protein
- Carried out by protein phosphatases
Phosphorylation is carried out by ___
Protein kinases
Dephosphorylation is carried out by ___
Protein phosphatases
What is an EPSP?
- Excitatory synapses can cause transient depolarization of the postsynaptic membrane
- This is called an excitatory postsynaptic potential (EPSP)
- It is not the same as an action potential
- One method for generating an EPSP is increasing sodium conductance
- Glutamate is an excitatory neurotransmitter → binding of glu usually causes postsynaptic
depolarization
Example of excitatory neurotransmitter
Glutamate
What is an IPSP?
- Inhibitory synapses hyperpolarize the membrane to bring it away from threshold through inhibitory postsynaptic potential (IPSP)
- One method for generating an IPSP is by increasing chloride conductance
- GABA and glycine are inhibitory neurotransmitters
Examples of inhibitory neurotransmitters
GABA and glycine
Can a neuron have both EPSPs and IPSPs?
Yes
EPSP and IPSP graph
What is synaptic potential?
- A transient change in postsynaptic membrane potential caused by NT release
- Does not necessarily bring neuron to threshold
- EPSP or IPSP
What is synaptic integration?
The process by which mutiple synaptic potentials combine in one postsynaptic neuron
What is quantal analysis of EPSP?
- The smallest unit of neurotransmission is
the release of the contents of one vesicle - The response of one vesicle is the miniature postsynaptic potential (mini)
- All EPSPs are the multiple of the mini ex. mini = 5 → EPSP = 5, 10, 15, 20,
What are the two ways in which synaptic integration can happen?
- Spatial summation
- Temporal summation
Spatial summation
Adding together many EPSPs generated at the same time on multiple synapses of a dendrite
Temporal summation
Adding together EPSPs that occur close together in time
How is synaptic summation achieved?
Each EPSP depolarizes the cell a little, so together they add together to reach threshold
Length constant
- The length constant (λ “lambda”) is a physical constant that quantifies the length that
depolarization travels before decaying to 37% of its original strength. This varies from neuron to
neuron depending on its physical properties. - The further away from the spike trigger zone on the axon, the less likely it is that an AP
will be generated. - Longer the length constant → neuron is better at preventing dissipation
of depolarization. - This also means a longer the length constant
→ more likely that an EPSP at a distant
synapse will cause an AP
The further away from the spike trigger zone on the axon, the ___ likely it is that an AP will be generated
Less
The longer the length constant, the ___ the neuron is at preventing dissipation of depolarization
Better
The longer the length constant, the ___ likely that an EPSP at a distant synapse will cause an AP
More
What is shunting inhibition?
- When an inhibitory synapse is activated close to the soma, the resultant IPSP can work to cancel out the incoming EPSP from an upstream excitatory synapse
- This is called shunting inhibition because this inhibitory synapse near
the soma can ”shunt” away excitation
and prevent the neuron from firing.
The neuron is held at a membrane
potential below threshold.
Post-synaptic effect of NT release
- Usually causes a change in post-synaptic Vm, and if there’s a strong enough change, it initiates an AP
- Time (“Kinetics”): how fast the change happens
○ Rapid (milliseconds)
○ Intermediate (seconds)
○ Slow (seconds to minutes)
● Effect: Postsynaptic cell becomes more depolarized or more hyperpolarized
● Depolarized = increased permeability to Na+, Ca2+
● Hyperpolarized = increased permeability to K+, Cl-
Depolarization or hyperpolarization in post-synaptic cell
- Depolarized = increased permeability to Na+, Ca2+
- Hyperpolarized = increased permeability to K+, Cl-
How does this trend align with what we know about these ion’s equilibrium potential?
Types of receptors
- Ligand-gated channels
- Autoreceptors
- G-protein coupled receptors
Ligand-gated channel are also known as ___
Ionotropic receptors
Ligand-gated channels
- NT is the ligand, or key, which opens the receptor
- Binding causes conformational change
- Conformational change allows flow of ions in
- Generally lower selectivity than VG channels
- Ex: Some ACh-gated channels let in both K + and Na +
- Faster but more transient effect on
postsynaptic cell than GPCRs
Autoreceptors
- On the presynaptic cell
- Activated by the NT they release
- Generally are GPCRs that then go on to regulate some aspect
of the cell (Ex: changing rate of NT synthesis)
A single NT can bind to both ___ and ___
Ligand-gated channels and G-protein coupled receptors
Activating the G-protein coupled receptor causes it to activate the ___
G-protein
What is the effect of activating the G-protein
- It initiates signal cascades by activating effector proteins (carry out an effect on the cell)
- Kinases
- G-protein gated channels
Effect of G-protein coupled receptor vs. ligand-gated channel
Slower, stronger, longer lasting, with
more diverse effects on the
postsynaptic cell than ligand-gated
ion channels.
Steps of GPCR
The G-protein is guanosine triphosphate (GTP)
binding protein. It has three subunits: alpha, beta,
gamma.
1. Inactive state: GDP (guanine diphosphate i.e.
GTP with one P removed) bound to
alpha-subunit
2. NT binding causes activation of the GPCR
3. Activated state: G-protein switches GDP for
GTP, becoming active and splitting into:
○ Alpha subunit + GTP
○ Beta/gamma complex
4. GTPase eventually converts GTP to GDP
Comparison: ionotropic vs. metabotropic receptors
Two methods of effects of GPCRs
- Method 1: G-protein directly affects activity of ion
channel. - Method 2: G-protein activates second messengers
(enzymes) which trigger downstream cascades,
ultimately causing changes in V m .
Why are second messengers important?
Simple amplification –> longer and wider effect in cell
Method 1: Direct effect on ion channels
Method 1: Direct effects on ion channels
The Shortcut Pathway
1. ACh binds to muscarinic receptor
2. Activates beta/gamma subunit
3. Beta/gamma subunit opens K +
channel
4. Efflux of K + ions causes
hyperpolarization
Other Points
● Slower than opening a ligand-gated K+ channel
● This is what was observed in the Otto Loewi
experiment!!!
● Also called membrane-delimited pathway b/c it
is localized at membrane
Method 2: cAMP 2nd Messenger Cascades
- Norepinephrine (NE) binds to beta-adrenergic receptor
- Alpha subunit dissociates and activates adenylyl cyclase (AC) - a membrane bound protein
- AC converts ATP to cAMP (second messenger)
- cAMP activates protein kinase A (PKA)
- PKA targets ion channels and other proteins
Example in cardiac muscle tissue, this cascade causes increase in rate and force of contraction of heart. Cardiac action potential is mediated by voltage-gated calcium channels
Continuation of AC function
Once activated, AC will make cAMP until the alpha subunit loses its GPT, so you can get multiple cAMPs for every active AC
cAMP 2nd messenger cascade (??)
Method 2: IP3/DAG 2nd messenger cascade
- Either NE or glu bind to and activate the GPCR
- The alpha-subunit of the G-protein splits off to active PLC
- PLC breaks PIP 2 (a phospholipid on the membrane) into…
○ DAG, which stays on the membrane and activates protein kinase C (PKC)
○ IP3, which departs the membrane and activates receptors on the smooth ER
○ These receptors cause the release of Ca2+ into the cytosol
○ Calcium reacts with calmodulin to form the calcium/calmodulin complex, which can
activate calcium-calmodulin-dependent kinase (Ca/CaMK)
Here, membrane
phospholipids are
broken down and serve
as the source of
intracellular second
messengers.
**Second messengers
underlined.
General methods of removal and termination of NTs
- Diffusion
- Reuptake
- Degradation
Desensitization
Diffusion (method of removal and termination of NT)
Neurotransmitter simply diffuses out of the synaptic cleft down its
concentration gradient. (Ex: nitric oxide (NO), which is a gaseous signaling
molecule)
Reuptake (method of removal and termination of NT)
NT is retrieved from the synaptic cleft for processing and re-use → can be
degraded by enzymes or transported into vesicles (Ex: 5-HT reuptake transporters,
which can be blocked pharmacologically as part of treatment for depression)
Degradation (method of removal and termination of NT)
Enzymatic inactivation of the NT (Ex: acetylcholinesterase destroys ACh)
Desensitization (method of removal and termination of NT)
Continued exposure to high concentration of NT makes channels stop
responding
Removal and termination of acetylcholine
- Enzyme AChE cleaves ACh into choline and acetic acid at synaptic cleft
- Choline transporter (co-transport with sodium) brings choline back into terminal for recylcing (this is the rate-limiting step)
Removal and termination of catecholamines
- No fast degradation process so dependent on uptake back into axon terminal
by Na + -dependent transporters - Can be loaded into vesicles for reuse or destroyed by monoamine oxidase (from
mitochondria outer membrane)
Removal and termination of serotonin
Same as catecholamines
Removal and termination of amino acids
Uptake into presynaptic terminals and glia with Na + -dependent transporters
→ can be degraded once inside terminals (ex. GABA by GABA transaminase)
Removal and Termination of NTs
Is feedback inhibition present in the synthesis pathway for serotonin and acetylcholine?
Ye
Reuptake of neurotransmitter involves ___
Transporting neurotransmitter molecules from the synaptic cleft into the presynaptic terminal
Where is acetylcholinesterase found?
Synaptic cleft
A drug that blocks acetylcholinesterase would cause an immediate ___ in signaling at cholinergic synapses
Increase
Which of the following responses takes the longest time to start letting ions through the membrane and keeps those ion channels open for the longest time?
a) activation of G-proteins that open ion channels
b) activation of protein kinases that open ion channels
b) activation of protein kinases that open ion channels
