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5BBM0218 Physiology and Pharmacology of CNS > L9: Neuropeptide transmitters > Flashcards

L9: Neuropeptide transmitters Flashcards

1
Q

What are some examples of neuropeptide transmitters?

A

Substance P
Neurokinins
Neuropeptide Y (NPY)
VIP
CGRP

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2
Q

How are neuropeptides synthesized and packaged in neurons?

A
  • Neuropeptides produced from large inactive precursors in the endoplasmic reticulum (ER).
  • then transferred to the Golgi apparatus.
  • in Golgi, neuropeptides are packaged into large dense core vesicles (LDCVs) along with enzymes that process the neuropeptides.
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3
Q

What is the biosynthesis process of Neuropeptide Y (NPY)?

A
  • NPY is derived from a gene with 4 exons.
  • Post-translational processing involves the addition of an NH2 group, producing the biologically active NPY.
  • CPON (C-terminal peptide of NPY) also formed during processing but remains inactive and is packaged with NPY.
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4
Q

How is Substance P formed?

A

-Substance P is encoded by the PPT I gene.
- Different combinations of gene products, including alpha and gamma PPT, predominate in the enteric nervous system, giving rise to Substance P

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5
Q

How is Neurokinin B (NKB) formed?

A

PPT II transcripts are translated into neurokinin B (NKB).

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6
Q

How do Substance P (SP) and NKB function as neurotransmitters?

A
  • Substance P (SP) and NKB are co-expressed and released to stimulate NK1 and NK2 receptors, respectively.
  • NKB is found in different neurons and stimulates NK3 receptors
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7
Q

Where are Substance P and Neurokinins predominantly expressed?

A
  • Substance P found in CNS, enteric nervous system (gastrointestinal innervation), and sensory nerves
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8
Q

How is neuropeptide degradation carried out, and what are the characteristics of enkephalinase (NEP)?

A
  • Neuropeptide degradation is nonspecific, and enzymes are non-selective.
  • Enkephalinase (NEP) is a neutral endopeptidase.
  • NEP degrades Met- and Leu-enkephalins, endorphins, Substance P (SP), Neurokinin A (NKA), VIP, NPY, and other peptides.
  • It is a major inactivator of neurokinins and NPY.
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9
Q

What is the consequence of having two hydrophobic amino acids next to each other in a neuropeptide?

A
  • When 2 hydrophobic AAs are adjacent to each other, the enzyme will cleave the peptide
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10
Q

What is the function of the inhibitor Phosphoramidon on NEP?

A
  • Phosphoramidon is an inhibitor of NEP.
  • It has a high affinity for NEPs and enhances the effects of neurokinins.
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11
Q

How is NPY degraded by other enzymes, and what are the consequences of this degradation?

A
  • NPY also degraded by other enzymes, such as aminopeptidase and dipeptidyl peptidase IV (DPP4).
  • DPP4 cleaves 2 amino acids from the N-terminus, producing NPY(3-36).
  • While this product does not inactivate the peptide, it has a high affinity for y2 receptors, leading to changes in signalling
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12
Q

What is the role of ACE (Angiotensin Converting Enzyme) in neuropeptide metabolism and inactivation?

A
  • ACE hydrolyzes enkephalins, Substance P, and neurotensin
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13
Q

Is there evidence of neuropeptides being taken up and re-used in the nervous system?

A
  • No - there’s no evidence that neuropeptides are taken up and re-used, and there is no peptide reuptake system
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14
Q

What happens during neurotransmitter release at low-frequency potentials?

A
  • At low-frequency potentials, there is a low influx of calcium.
  • The small synaptic vesicles (SSVs) fuse with the membrane during release
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15
Q

When does co-release of neurotransmitters occur?

A
  • co-release occurs when nerves are activated at high frequency or in a pulsatile manner.
  • at high-frequency potentials, there is a bigger influx of calcium.
  • the small synaptic vesicles (SSVs) and large dense core vesicles (LDCVs) fuse with the membrane during co-release
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16
Q

What is the varicosity’s condition during co-release?

A

varicosity is free of Schwann cells during co-release

17
Q

What are the two types of co-transmission, and how do they work?

A
  1. Neuromodulation: NT can modulate its release or co-transmitter release via pre-synaptic receptors.
  2. Co-release: Occurs when nerves are activated at high frequency or in a pulsatile manner. At high-frequency potentials, there is a bigger influx of calcium, leading to the fusion of SSVs and LDCVs
18
Q

What are the co-transmitters involved in parasympathetic nerves innervating the salivary glands, and how do they work together?

A

-VIP (Vasoactive Intestinal Peptide) & Ach (Acetylcholine) are the co-transmitters
- At low frequency, only Ach has an effect, acting on muscarinic receptors to release saliva & cause minor dilation of blood vessels
- At high frequency, co-release of VIP with Ach occurs.
-VIP activates VIP receptors, leading to an enhanced post-junctional muscarinic acinar response & ↑ release of Ach by acting on VIP pre-junctional receptors

19
Q

What are the co-transmitters involved in sympathetic nerves innervating the smooth muscle, and how do they work together?

A
  • NPY & NA (Noradrenaline) are the co-transmitters
  • At low frequency, NA is released, and it acts on a2 receptors to inhibit further NA release.
  • At high frequency, NPY is released & it activates Y1 receptors (post-synaptic), amplifying the effect of a1 receptors. Y2 receptors (pre-synaptic) are activated to cause the inhibition of NA and NPY release, leading to vasoconstriction
20
Q

What are the characteristics of neurons that only release neuropeptides?

A
  • Not all neurons express classic neurotransmitters; some only release neuropeptides.
  • Peptide receptors are G-coupled Gi/o, and their response is slower compared to ionotropic receptors.
21
Q

What is the effect of NPY on its receptors, and how is it metabolized?

A
  • NPY has an inhibitory effect & high affinity for the Y1 receptor.
  • NPY metabolized by DPPIV, which removes 2 amino acids from the sequence. The resulting product has affinity for the Y2 receptor but not the Y1 receptor.
  • NPY and NPY(3-36) have low affinity for the Y4 receptor.
22
Q

What are the roles of NPY in the PNS & CNS?

A
  • In PNS = NPY acts as vasoconstrictor and inhibits pain by inhibiting the release of substance P (SP) and neurokinin A (NKA) in the dorsal horn.
  • In CNS = NPY stimulates feeding but also exhibits inhibitory effects - such as anxiolytic, anti-epileptic, and sedative effects.
23
Q

What are the roles of SP, NKA, and CGRP in the spinal cord and intestine?

A
  • SP and NKA are major sensory neurotransmitters in the spinal cord and intestine.
  • they mediate pain and cause smooth muscle contraction.
  • CGRP appears to have an “enhancer” role when co-localized with SP and NKA
24
Q

What are the roles of substance P (SP) and neurokinin A (NKA) in the spinal cord and gut?

A
  • spinal cord = SP and NKA stimulate specific neurons to increase spinal excitability.
  • gut = SP and NKA act on smooth muscle and interstitial cells.
  • SP acts through the NK1 receptor
  • NKA acts through the NK2 receptor.
    Each receptor is coupled to Gq, leading to an The mutated channel lacks calcium permeability.
    It still allows some sodium entry but no calcium entry, leading to reduced GABA release in intracellular Ca2+
25
Q

What are the therapeutic implications of neuropeptide receptors for drug development?

A
  • Y1 antagonists can be used as anti-obesity and anti-inflammatory agents
  • NK receptors, such as aprepitant (NK1 antagonist) used as anti-emetics in treatment of cancer.
  • DPP4 inhibitors, like sipagliptin used for treatment of type II diabetes
26
Q

What is the genetic linkage and gene location associated with the mutation in nAChR?

A
  • Genetic Linkage: 20q13.2-13.3
  • Gene codes for: alpha4 subunit of the nAChR
27
Q

What is the specific point mutation associated with the nAChR?

A
  • Point Mutation: S247F
  • The mutation is located at the pore region of the nAChR
28
Q

What are the effects of the S247F mutation on the nAChR?

A
  • mutated channel lacks Ca2+ permeability
  • still allows some Na+ entry but no Ca2+ entry, leading to reduced GABA release
  • mutated channel exhibits increased desensitization
    It shows slow recovery from desensitization.
    The mutated channel has no calcium permeability.
29
Q
A

5BBM0218 Physiology and Pharmacology of CNS (17 decks)

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