Lecture 4: NEUROMODULATORS

Question 1

Define Neuromodulation

Answer 1

A change in the state of a neuron or a group of neurons that alters its response to a subsequent stimulation

Question 2

Neuromodulators commonly act on

Answer 2

the release of neurotransmitters from
the axon terminals/presynaptic neuron and/or postsynaptic receptors

Question 3

2 type of Neuromodulation… techniques..

Answer 3

A: Point-to-point neurotransmission

vs

B: Neuromodulation and volumetric neurotransmission

Question 4

A: Point-to-point neurotransmission

vs

B: Neuromodulation and volumteric neurotransmission

Answer 4

A:

1. INHIBITORY
   Presynaptic neuron = depolarisation
   ….
   Postsynaptic neuron = hyperpolarisation

or
2. EXCITATORY Presynaptic neuron = depolarisation
….
Postsynaptic neuron = depolarisation

B: Look at slide 3

Question 5

Most neuromodulators bind to….. and therefore….

Answer 5

Most neuromodulators bind to ‘GPCRs’ and therefore …

-act on a slower timescale relative to neurotransmitters that bind to ionotropic receptors

Question 6

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

Answer 6

1. acetylcholine,
2. dopamine,
3. serotonin,
4. cannabinoids,
5. nitric oxide

Question 7

what do neurotransmitters and neuromodulators bind to? 2

Answer 7

1. Many neurotransmitters and neuromodulators bind to ‘GPCRs’
2. Some neurotransmitters and neuromodulators bind to:
   “ ion channels (ionotropic) and GPCRs (metabotropic)”

Question 8

NEUROMODULATORS:

EXPLAIN RECEPTORS AND STRUCTURAL FEATURES

CLASS A: rhodopsin family

Answer 8

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)

Question 9

NEUROMODULATORS:

EXPLAIN RECEPTORS AND STRUCTURAL FEATURES

CLASS B: secretin/glucagon receptor family.

Answer 9

RECEPTORS: for PEPTIDE HORMONES, including SECRETIN, GLUCAGON, CALCITONIN

STRUCTURAL FEATURES:
1. Intermediate Extracellular tail incorporating ligand-binding domian

Question 10

NEUROMODULATORS:

EXPLAIN RECEPTORS AND STRUCTURAL FEATURES

CLASS C: metabotropic glutamate receptor/calcium sensor family

Answer 10

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

Question 11

Explain the 2 Stages of Neuromodulators

Answer 11

1. RESTING STATE
   - G proteins coupled to receptors
2. Agonist bind to GPCR
   - G proteins coupled to receptor separate and interact/bind with their targets

Question 12

draw and label the 2 Stages of Neuromodulators

Answer 12

slide 6

Question 13

What are the roles and characteristics of adenosine in the brain? = 5 and explain

Answer 13

1. Sleep Regulation and Energy Metabolism:
   Adenosine regulates sleep homeostasis and energy metabolism in neurons.
2. Neuromodulatory Function:
   It acts as a powerful neuromodulator in cholinergic neurotransmission in the brain.
3. Metabolite of ATP Degradation:
   Adenosine is a metabolite of intracellular ATP degradation, increasing during high periods of neuronal activity.
4. Production Mechanism:
   ATPases in the membrane degrade released ATP to produce adenosine, which is not stored in vesicles.
5. Receptor Binding:
   Adenosine binds to G protein-coupled receptors (GPCRs), specifically AxARs, both pre- and postsynaptically, as well as on glia.

Question 14

How does adenosine exert its neuromodulatory effects, specifically through A1 adenosine receptors (A1ARs), on cortical pyramidal neurons? = 3

Answer 14

1. ‘Neuromodulatory Mechanism’ :
   - A1 adenosine receptors (A1ARs) hyperpolarize cortical pyramidal neurons.
2. ‘Effect on Potassium Channels:’
   - A1ARs increase the probability of potassium channel opening.
3. ‘Effect on Glutamate Release’ :
   - They decrease the release of calcium-dependent glutamate by reducing the probability of calcium channel opening.

Question 15

What is acetylcholine’s role as a neurotransmitter in the periphery? = 2

Answer 15

1. Neuromuscular Junction:
2. Acetylcholine (ACh) serves as the primary excitatory neurotransmitter at the neuromuscular junction in the periphery.

Question 16

What role does acetylcholine play as a neuromodulator in the brain? = 2

Answer 16

1. Cholinergic Neurotransmission:
2. In the brain, acetylcholine acts as a powerful neuromodulator in cholinergic neurotransmission.

Question 17

How does acetylcholine affect neurotransmitter release, and what factors influence its impact on neural activity? = 2

Answer 17

1. Impact on Neurotransmitter Release:
2. 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.

Question 18

What are some suggested roles of acetylcholine neuromodulation in the brain? = 3

Answer 18

Suggested Roles:

1. Fine-tuning circuits for “uncertainty.”
2. Reinforcing neuronal loops and cortical synaptics during learning.
3. Fear conditioning.

Question 19

Where are acetylcholine receptors located in the brain, and what are the main types of receptors? = 4

Answer 19

1. Location:
   Acetylcholine receptors are found both pre- and postsynaptically in the brain.
2. Types of Receptors:
   Acetylcholine signals through
3. muscarinic (mAChRs) and
4. nicotinic (nAChRs) receptors.

Question 20

What are the neuromodulatory actions produced by muscarinic acetylcholine receptors (mAChRs)? = 2

Answer 20

1. Neuromodulatory Actions:
2. ‘mAChRs produce a range of neuromodulatory actions in the brain’

Question 21

How do presynaptic M2/M4 mAChRs affect cholinergic terminals, and what is their impact on glutamate release? = 4

Answer 21

1. Impact on Cholinergic Terminals:
   …2. Presynaptic M2/M4 mAChRs inhibit cholinergic terminals through autoreception.
2. Effect on Glutamate Release:
   ….4. They reduce glutamate release.

Question 22

What are the effects of M1/M5 mAChRs on dopamine release and cortical pyramidal neurons? = 4

Answer 22

1. Dopamine Release:
   2…. M1/M5 mAChRs promote dopamine release in the striatum.
2. Impact on Cortical Pyramidal Neurons:
   4….. They increase the excitability of cortical pyramidal neurons.

Question 23

What are the characteristics and distribution of nicotinic acetylcholine receptors (nAChRs) in the brain? = 4

Answer 23

1. Characteristics:
   2….. nAChRs are non-selective excitatory cation channels.
2. Distribution:
   ….4. They are dispersed throughout the neuronal membrane, including pre- and postsynaptic regions, soma, and axons.

Question 24

What is the difference in neuromodulation speed between nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs)?… 2

Answer 24

1. 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.

Question 24

How does activation of nicotinic acetylcholine receptors (nAChRs) influence neurotransmitter release, and what factors contribute to its variability?

= 4

Answer 24

1. Impact on Neurotransmitter Release:
   2…. Activation of nAChRs can increase the release of various neurotransmitters, such as glutamate, GABA, dopamine, and acetylcholine.
2. Variability:
   4….. The effect varies depending on neuron subtype and neuronal circuit.

Question 25

How do neuropeptides differ from amino acid neurotransmitters in terms of their release sites?

Answer 25

Difference in Release Sites:

Neuropeptides are more commonly released at sites outside of the synapse compared to amino acid neurotransmitters like GABA and glutamate.

Question 26

What is the current debate surrounding the diffusion range of neuropeptides compared to amino acid neurotransmitters?

Answer 26

Debated Aspect:
It is still debated, but it is suggested that neuropeptides may travel further from their release site than amino acid neurotransmitters.

Question 27

Can you provide an example of neuropeptides traveling long distances to exert their effects?

Answer 27

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.

Question 28

What type of receptors do most neuropeptides bind to, and what is the primary signaling mechanism involved? = 2

Answer 28

1. ‘Receptor Type’:
   Most neuropeptides bind to G protein-coupled receptors (GPCRs).
2. ‘Signaling Mechanism’:
   Neuropeptide binding to GPCRs activates multiple intracellular signaling pathways.

Question 29

Where are neuropeptide receptors typically distributed within neuronal structures?

Answer 29

Distribution:
Neuropeptide receptors are distributed throughout the neuronal structure, including pre- and postsynaptic regions, soma, and axons.

Question 30

What is the variability in neuropeptide receptor activation, and can you provide examples? = 3

Answer 30

1. Variability:
2. Neuropeptides may activate multiple receptors in multiple locations, as seen with Neuropeptide Y (NPY).
3. Some neuropeptides, such as Kisspeptin, act on single receptors.

Question 31

What is a notable characteristic of neurons that release neuropeptides in addition to fast-acting amino acid transmitters?

Answer 31

Characteristic:
— Most neurons that release neuropeptides also release fast-acting amino acid transmitters, suggesting a dual mode of signaling.

Question 32

How do neuropeptides modulate presynaptic neurotransmitter release?

Answer 32

Modulation:

Neuropeptides can either INCREASE or DECREASE PRESYNAPTIC NEUROTRANSMITTER RELEASE

Question 33

What factors contribute to the specificity of neuropeptide-mediated presynaptic modulation?

Answer 33

Specificity Factors:

Neuropeptide-mediated presynaptic modulation is influenced by the peptide type, cell type, and neural circuit involved.

Question 34

What are some of the pathways through which neuropeptides modulate presynaptic neurotransmitter release?

Answer 34

Modulation Pathways:

– Neuropeptides exert presynaptic modulation through multiple pathways, including changes toION CHANNEL ACTIVATION AND ION FLOW

Question 35

How is nitric oxide (NO) produced in the brain, and what triggers its production?

Answer 35

Production Mechanism:

– NMDA receptor activation triggers the production of nitric oxide (NO)

Question 36

What is a notable characteristic of nitric oxide in terms of its release and diffusion? =3

Answer 36

1. Release and Diffusion:
2. Nitric oxide is not released by exocytosis;
3. instead, it diffuses from presynaptic nerve terminals into the extracellular space and nearby cells.

Question 37

How does nitric oxide exert its effects on biological pathways? =3

Answer 37

1. Mechanism of Action:
2. Nitric oxide does not bind to receptors;
3. instead, it binds to enzymes, leading to the activation of a range of biological pathways.

Question 38

What are chemokines, and what are they primarily produced and released by?

Answer 38

Definition:
Chemokines are small proteins or large peptides.

Source:
They are primarily produced and released by immune cells.

Question 39

What types of molecules are included in the category of chemokines?

Answer 39

Molecule Types:
Chemokines are a subset of cytokines, which also include interleukins, interferons, and tumor necrosis factors.

Question 40

What is a relatively new concept regarding the role of chemokines, and what does it suggest about their presence in the brain?

Answer 40

• 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.

Question 41

Where are chemokine receptors typically located, and how do chemokines enter the nervous system? = 4

Answer 41

1. Receptor Location:
   2….. Chemokine receptors are located both pre- and postsynaptically and on glial cells.
2. Entry into Nervous System:
   4…. Chemokines can be released by cells in the nervous system or enter through the bloodstream from peripheral release

Question 42

What effects can chemokines have on neurotransmitter release, and what are some additional effects they may produce? = 4

Answer 42

1. Neurotransmitter Modulation:
   — Some chemokines are known to modulate the release of GABA.
2. Additional Effects:
   — Chemokines can produce either a protective effect or an apoptotic effect, or both.