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physiology and pharma > L9 - neuropeptide traansmitters > Flashcards

L9 - neuropeptide traansmitters Flashcards

1
Q

what are the families of neuropeptides

A
  1. neurokinins (including substance P) -> sensory transmitters
  2. enkephalins and opioid peptides
  3. Neuropeptide Y (NPY) and analogues
  4. vasoactive intestinal Polypeptide (VIP)
  5. CGRP (calcitonin gene related peptide)

many more

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2
Q

describe neuropeptide synthesis

A

they are cleaved from larger inactive precursors by enzymes then transported to golgi for packaging into large dense- core vesicles

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3
Q

how was substance P discovered

A

von euler and goddum were studying ACh when they discovered a substance that was insensitive to atropine but could cause elevated blood pressure and gut smooth muscle contraction

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4
Q

what effect do enkephalins have?

A

analgesia

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5
Q

are expression levels of neuropeptides constant

A

no they can vary depending on pathology, or nerve injury

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6
Q

describe the processing of NPY

A

gene transcribed into precursor which is cleaved giving NPY and CPON (C-terminal peptide of NPY) which is inactive

precursor must have an NH2 group added post-transcriptionally to its C terminal for NP to be active

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7
Q

what two genes are responsible for production of Substance P and NKs

A

PPT1
PPT2

preprotachykinin 1&2

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8
Q

what are the main neuropeptides produced by PPT1

A

substance P and NKA
often co expressed

(predominantly found in enteric nervous system)

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9
Q

what are the main neuropeptides produced by PPT2

A

NKB

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10
Q

where is substance P found

A

CNS
ENS
sensory nerves

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11
Q

describe the degradation of neuropeptides

A

non specific unlike other NTs

one enzyme can degrade many neuropeptides

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12
Q

give example of enzyme that degrades neuropeptides and give examples of what it can degrade

A

enkephalinase

can degrade:

  • Met and Leu enkephalins
  • SP
  • NKA
  • NKB
  • NPY
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13
Q

describe the mechanism of neuropeptide degradation by enkephalinase (NEP)

NEP -> natural endopeptidase

A
  1. enkephalinase cleaves the protein between a Hphobic residue and a tyrosine/phenylalanine

if the peptide doesnt have this in its sequence it wont be degraded by enkephalinase

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14
Q

what effect does phosphoramidon have

A

phosphoramidon is a high affinity NEP inhibitor and so will prolong and exaggerate effects of Neuropeptides

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15
Q

name a NEP inhibitor

A

phosphoramidon

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16
Q

what else, other than NEP can degrade NPY

A

aminopeptidase DPPIV

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17
Q

describe mechanism of degradation of NPY by aminopeptidase DPPIV

A
  1. aminopeptidase cleaves 2 AAs from the N terminal of NPY

2. this cleavage forms NPY 3-36

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18
Q

what effect does amiopeptidase degradation have on NPY receptor activation

A

NPY can activate receptors Y1 and Y2

after degradation to NPY(3-36), this peptide can activate Y2 receptors but not Y1

so aminopeptidase degradation doesnt fully inactivate NPY but changes its singalling ability

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19
Q

are neuropeptides re-uptaken

A

no, just degraded

20
Q

what receptors are activated by NPY 3-36

A

Y2 only

21
Q

what type of vesicles are normal NTs stored in

what type of vesicles are neuropeptides stored in

A

small clear synaptic vesicles

large dense core vesicles

22
Q

when does co-release of neuropeptides and NTs occur?

A

when there is a higher frequency of APs, the increase in [Ca2+] is more widespread in the terminal, so synaptic vesicles and neuropeptide vesicles are both exocytosed.

23
Q

under what conditions does co-release of NT and neuropeptides not occur?

A

when there is a lower frequency of APs, the elevated Ca2+ levels are more local, resulting in only the exocytosis of NT vesicles

24
Q

why does low frequency APs and local Ca2+ elevation only cause NT release rather than co release of NT and neuroptides?

A

because the NT synaptic vesicles are found closer to the membrane, the neuropeptide vesicles dont experience the elevated Ca2+ levels as they are further from the membrane

25
Q

differences between NT transmission and neuropeptide transmission

A

neuropeptides can act across larger distances - distance between pre&post membranes in periphery is much longer than in the CNS

NPs are slower acting than NTs for this reason

26
Q

what is neuormodulation (in regards to NPs)

A

can be presynaptic -> the released NP acts presynaptically to inhibit / increase release (of itself or the primary NT)

can be postsynaptic -> NP acts on post synaptic receptors to alter the primary response of the released NT

27
Q

describe the effects of VIP and ACh in PNS nerves of salivary glands as an example of cotransmission / neuromodulation

A
  1. at low frequency of stimulation, response is normal ACh released acts on muscarinic receptors causing salivary secretion and minor vasodilation
  2. at high frequency of stimulation VIP is co-released with ACh which:
    - presynaptically increases ACh release
    - enhances post-synaptic response (increased vaodilation)
28
Q

describe the effects of NPY and NA in SNS smooth muscle as an example of cotransmission / neuromodulation

A
  1. low frequency -> stimulation preferentially releases NA over NPY resulting in vasoconstriction via a1 receptors
  2. high frequency, intermittent stimulation is optimal for NPY release. which has the following effects:

low [NPY] potentiates NA induced vasoconstriction
high [NPY] acts on Y1 receptors (post synaptically) to cause vasoconstriction and acts on Y2 receptors (presynaptically) to inhibit NPY and NA via negative feedback

29
Q

how are the effects of NA affected by low concenrtrations of NPY (co released)

A

NPY enhances the NA induced vasoconstriction

30
Q

what effects do high [NPY] have (NA co release)

A

act on Y1 receptors post synaptically to cause vasoconstriction

act on Y2 receptors presynaptically to inhibit NPY and NA release from presynaptic terminal (negative feedback)

31
Q

what is the optimal stimulation frequency for NPY release

A

high frequency, intermittent stimulation

32
Q

do all peptide neurones also release a classic transmitter?

A

no

for example oxytocin is released from magnocellular neurones on its own

33
Q

what are the effects of NPY

in PNS
in CNS

A

PNS

  • potent vasoconstrictor via Y1 receptors of vascular smooth muscle
  • analgesia via inhibition of SP and NKA release in dorsal horn via Y2 receptors

CNS

  • stimulates feeding via Y1 and Y5
  • its inhibitory effects make it a sedative (via Y1) and antiepileptic via Y2 (in neurones)
34
Q

what type of receptors are ALL neuropeptide receptors

A

GPCRs

35
Q

what are the NPY receptors called and what are they coupled to

A

Y receptors

Gi/o

36
Q

describe how NPY causes vasoconstriction

A
  1. acts on Y1 receptors of vascular smooth muscle which can cause increase in intracellular [Ca2+]
  2. this causes vasoconstriction
37
Q

explain why NPY activation of Y1 receptors can cause vasoconstriction, but also have sedative effects

A

Y1 recepotrs in different locations (smooth muscle vs neurones) have different effects

38
Q

explain how NPY causes inhibition when binding to
Y1
Y2
receptors in CNS

A

binding to Y1 (post synaptic) causes opening of K+ channels -> hyperpolarisation

binding to y2 (pre synaptic) can block NT release or open Ca2+ channels

39
Q

what are Neurokinin receptors coupled to?

A

Gq

40
Q

how many NK receptors are there? name them

A

3

NK1-3

41
Q

what NK receptor has the highest affinity for SP

A

NK1

42
Q

NKA has the highest affinity for which NK receptor?

A

NK2

43
Q

NKB has the highest affinity for which NK receptor?

A

NK3

44
Q

what are the effects of NKR activation? (SP and NKA)

A

increase intracellular [Ca2+] in neuronal and non neuronal cells

so cause vasoconstriction
increase excitability in spinal cord (sensory NTs)

major sensory NTs in spinal cord and intestine

45
Q

what are possible future therapeutics targetting Y receptors

A

y1 -> anti hypertensives, anti-epileptics,

Y5 -> anti-inflammatory

other Y receptors -> anti-inflammatory

46
Q

describe a drug / therapeutic targeting NK receptors

A

NK1 antagonists are proven anti-emetics (aprepitant)

often used in chemotherapy to treat sickness

47
Q

explain the use of DPPIV inhibitors

A

inhibition of aminopeptidase (DPPIV) increases the half life of GLP-1

GLP-1 increases glucose dependant insulin release and pancreatic B cell number

increasing its half life useful treatment in type 2 diabetes

physiology and pharma (18 decks)

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