Lecture 4: NEUROMODULATORS Flashcards
Define Neuromodulation
A change in the state of a neuron or a group of neurons that alters its response to a subsequent stimulation
Neuromodulators commonly act on
the release of neurotransmitters from
the axon terminals/presynaptic neuron and/or postsynaptic receptors
2 type of Neuromodulation… techniques..
A: Point-to-point neurotransmission
vs
B: Neuromodulation and volumetric neurotransmission
A: Point-to-point neurotransmission
vs
B: Neuromodulation and volumteric neurotransmission
A:
- INHIBITORY
Presynaptic neuron = depolarisation
….
Postsynaptic neuron = hyperpolarisation
or
2. EXCITATORY Presynaptic neuron = depolarisation
….
Postsynaptic neuron = depolarisation
B: Look at slide 3
Most neuromodulators bind to….. and therefore….
Most neuromodulators bind to ‘GPCRs’ and therefore …
-act on a slower timescale relative to neurotransmitters that bind to ionotropic receptors
Most neuromodulators bind to GPCRs and therefore act on a slower timescale relative to neurotransmitters that bind to ionotropic receptors
Well known examples include 5
- acetylcholine,
- dopamine,
- serotonin,
- cannabinoids,
- nitric oxide
what do neurotransmitters and neuromodulators bind to? 2
- Many neurotransmitters and neuromodulators bind to ‘GPCRs’
- Some neurotransmitters and neuromodulators bind to:
“ ion channels (ionotropic) and GPCRs (metabotropic)”
NEUROMODULATORS:
EXPLAIN RECEPTORS AND STRUCTURAL FEATURES
CLASS A: rhodopsin family
Receptors:
1. LARGEST GROUP
2. RECEPTORS: for most AMINE NEUROTRANSMITTERS, many NEUROPEPTIDES, PURINES, PROSTANOIDS, CANNABINOIDS, etc.
STRUCTURAL FEATURES:
1. Short extracellular (N-terminal) tail
2. LIGAND binds to TRANSMEMBRANE HELICES (AMINES) OR to EXTRACELLULAR LOOPS (PEPTIDES)
NEUROMODULATORS:
EXPLAIN RECEPTORS AND STRUCTURAL FEATURES
CLASS B: secretin/glucagon receptor family.
RECEPTORS: for PEPTIDE HORMONES, including SECRETIN, GLUCAGON, CALCITONIN
STRUCTURAL FEATURES:
1. Intermediate Extracellular tail incorporating ligand-binding domian
NEUROMODULATORS:
EXPLAIN RECEPTORS AND STRUCTURAL FEATURES
CLASS C: metabotropic glutamate receptor/calcium sensor family
Receptors:
1. SMALL GROUP.
2. METABROTROPIC GLUTAMATE RECEPTORS
3. GABA (b) receptors
4. Ca+2 SENSING RECEPTORS
STRUCTURAL FEATURES:
1. LONG extracellular tail incorporating ligand-binding Domain
Explain the 2 Stages of Neuromodulators
- RESTING STATE
- G proteins coupled to receptors - Agonist bind to GPCR
- G proteins coupled to receptor separate and interact/bind with their targets
draw and label the 2 Stages of Neuromodulators
slide 6
What are the roles and characteristics of adenosine in the brain? = 5 and explain
- Sleep Regulation and Energy Metabolism:
Adenosine regulates sleep homeostasis and energy metabolism in neurons. - Neuromodulatory Function:
It acts as a powerful neuromodulator in cholinergic neurotransmission in the brain. - Metabolite of ATP Degradation:
Adenosine is a metabolite of intracellular ATP degradation, increasing during high periods of neuronal activity. - Production Mechanism:
ATPases in the membrane degrade released ATP to produce adenosine, which is not stored in vesicles. - Receptor Binding:
Adenosine binds to G protein-coupled receptors (GPCRs), specifically AxARs, both pre- and postsynaptically, as well as on glia.
How does adenosine exert its neuromodulatory effects, specifically through A1 adenosine receptors (A1ARs), on cortical pyramidal neurons? = 3
- ‘Neuromodulatory Mechanism’ :
- A1 adenosine receptors (A1ARs) hyperpolarize cortical pyramidal neurons. - ‘Effect on Potassium Channels:’
- A1ARs increase the probability of potassium channel opening. - ‘Effect on Glutamate Release’ :
- They decrease the release of calcium-dependent glutamate by reducing the probability of calcium channel opening.
What is acetylcholine’s role as a neurotransmitter in the periphery? = 2
- Neuromuscular Junction:
- Acetylcholine (ACh) serves as the primary excitatory neurotransmitter at the neuromuscular junction in the periphery.
What role does acetylcholine play as a neuromodulator in the brain? = 2
- Cholinergic Neurotransmission:
- In the brain, acetylcholine acts as a powerful neuromodulator in cholinergic neurotransmission.
How does acetylcholine affect neurotransmitter release, and what factors influence its impact on neural activity? = 2
- Impact on Neurotransmitter Release:
- Acetylcholine tends to increase neurotransmitter release but can either promote or decrease neural activity depending on the system and the neuronal subtype it acts on.
What are some suggested roles of acetylcholine neuromodulation in the brain? = 3
Suggested Roles:
- Fine-tuning circuits for “uncertainty.”
- Reinforcing neuronal loops and cortical synaptics during learning.
- Fear conditioning.
Where are acetylcholine receptors located in the brain, and what are the main types of receptors? = 4
- Location:
Acetylcholine receptors are found both pre- and postsynaptically in the brain. - Types of Receptors:
Acetylcholine signals through - muscarinic (mAChRs) and
- nicotinic (nAChRs) receptors.
What are the neuromodulatory actions produced by muscarinic acetylcholine receptors (mAChRs)? = 2
- Neuromodulatory Actions:
- ‘mAChRs produce a range of neuromodulatory actions in the brain’
How do presynaptic M2/M4 mAChRs affect cholinergic terminals, and what is their impact on glutamate release? = 4
- Impact on Cholinergic Terminals:
…2. Presynaptic M2/M4 mAChRs inhibit cholinergic terminals through autoreception. - Effect on Glutamate Release:
….4. They reduce glutamate release.
What are the effects of M1/M5 mAChRs on dopamine release and cortical pyramidal neurons? = 4
- Dopamine Release:
2…. M1/M5 mAChRs promote dopamine release in the striatum. - Impact on Cortical Pyramidal Neurons:
4….. They increase the excitability of cortical pyramidal neurons.
What are the characteristics and distribution of nicotinic acetylcholine receptors (nAChRs) in the brain? = 4
- Characteristics:
2….. nAChRs are non-selective excitatory cation channels. - Distribution:
….4. They are dispersed throughout the neuronal membrane, including pre- and postsynaptic regions, soma, and axons.
What is the difference in neuromodulation speed between nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs)?… 2
- Neuromodulation Speed:
2….. Neuromodulation via nAChRs is faster than that via mAChRs due to the ionotropic nature of nAChRs compared to the metabotropic nature of mAChRs.
How does activation of nicotinic acetylcholine receptors (nAChRs) influence neurotransmitter release, and what factors contribute to its variability?
= 4
- Impact on Neurotransmitter Release:
2…. Activation of nAChRs can increase the release of various neurotransmitters, such as glutamate, GABA, dopamine, and acetylcholine. - Variability:
4….. The effect varies depending on neuron subtype and neuronal circuit.
How do neuropeptides differ from amino acid neurotransmitters in terms of their release sites?
Difference in Release Sites:
Neuropeptides are more commonly released at sites outside of the synapse compared to amino acid neurotransmitters like GABA and glutamate.
What is the current debate surrounding the diffusion range of neuropeptides compared to amino acid neurotransmitters?
Debated Aspect:
It is still debated, but it is suggested that neuropeptides may travel further from their release site than amino acid neurotransmitters.
Can you provide an example of neuropeptides traveling long distances to exert their effects?
Leptin, a neuropeptide released from the stomach, acts on targets in the brain, suggesting that
neuropeptides may have the ability to travel from distant sites to exert their effects.
What type of receptors do most neuropeptides bind to, and what is the primary signaling mechanism involved? = 2
- ‘Receptor Type’:
Most neuropeptides bind to G protein-coupled receptors (GPCRs). - ‘Signaling Mechanism’:
Neuropeptide binding to GPCRs activates multiple intracellular signaling pathways.
Where are neuropeptide receptors typically distributed within neuronal structures?
Distribution:
Neuropeptide receptors are distributed throughout the neuronal structure, including pre- and postsynaptic regions, soma, and axons.
What is the variability in neuropeptide receptor activation, and can you provide examples? = 3
- Variability:
- Neuropeptides may activate multiple receptors in multiple locations, as seen with Neuropeptide Y (NPY).
- Some neuropeptides, such as Kisspeptin, act on single receptors.
What is a notable characteristic of neurons that release neuropeptides in addition to fast-acting amino acid transmitters?
Characteristic:
— Most neurons that release neuropeptides also release fast-acting amino acid transmitters, suggesting a dual mode of signaling.
How do neuropeptides modulate presynaptic neurotransmitter release?
Modulation:
Neuropeptides can either INCREASE or DECREASE PRESYNAPTIC NEUROTRANSMITTER RELEASE
What factors contribute to the specificity of neuropeptide-mediated presynaptic modulation?
Specificity Factors:
Neuropeptide-mediated presynaptic modulation is influenced by the peptide type, cell type, and neural circuit involved.
What are some of the pathways through which neuropeptides modulate presynaptic neurotransmitter release?
Modulation Pathways:
– Neuropeptides exert presynaptic modulation through multiple pathways, including changes toION CHANNEL ACTIVATION AND ION FLOW
How is nitric oxide (NO) produced in the brain, and what triggers its production?
Production Mechanism:
– NMDA receptor activation triggers the production of nitric oxide (NO)
What is a notable characteristic of nitric oxide in terms of its release and diffusion? =3
- Release and Diffusion:
- Nitric oxide is not released by exocytosis;
- instead, it diffuses from presynaptic nerve terminals into the extracellular space and nearby cells.
How does nitric oxide exert its effects on biological pathways? =3
- Mechanism of Action:
- Nitric oxide does not bind to receptors;
- instead, it binds to enzymes, leading to the activation of a range of biological pathways.
What are chemokines, and what are they primarily produced and released by?
Definition:
Chemokines are small proteins or large peptides.
Source:
They are primarily produced and released by immune cells.
What types of molecules are included in the category of chemokines?
Molecule Types:
Chemokines are a subset of cytokines, which also include interleukins, interferons, and tumor necrosis factors.
What is a relatively new concept regarding the role of chemokines, and what does it suggest about their presence in the brain?
- New Concept:
The idea of chemokines acting as neuromodulators is relatively new. - Implication:
If chemokines are involved in non-immune functions, they should be present in the intact brain.
Where are chemokine receptors typically located, and how do chemokines enter the nervous system? = 4
- Receptor Location:
2….. Chemokine receptors are located both pre- and postsynaptically and on glial cells. - Entry into Nervous System:
4…. Chemokines can be released by cells in the nervous system or enter through the bloodstream from peripheral release
What effects can chemokines have on neurotransmitter release, and what are some additional effects they may produce? = 4
- Neurotransmitter Modulation:
— Some chemokines are known to modulate the release of GABA. - Additional Effects:
— Chemokines can produce either a protective effect or an apoptotic effect, or both.
