Nitroxigenic neurotransmission

Question 1

What is the criteria for NTs?

Answer 1

• Synthesis on demand
• Storage in synaptic vesicles
• Released by exocytosis
• Actions at receptors on postsyn membrane
• Inactivation/uptake

Question 2

What are the properties of Nitric oxide?

Answer 2

• Is a gas and free radical
• Labile (free radicle=Highly reactive)
• Very short half life
• Membrane permanent
• No storage pools of NO
• Diffuses rapidly from site of production
• No receptors (diffuses into targets)
• Removal - Hb, superoxide
• Perfectly suited for short range transmission

Question 3

What are the problems with NO?

Answer 3

• NO only meets 2 of the criteria whcih means we need to rething definition of NT

Question 4

What is NOS?

Answer 4

• We can’t generate antagonists or antibodies for a gas, so instead we use the enzymes that prod NO to test it
• Neuronal NOS
• Inducible NOS
• Endothelial NOS

Question 5

How does NOS work?

Answer 5

• NOS oxidises arginine to become citrulline and NO
• Requires Ca2+ an calmodulin

Recognition sites for multiple electron donors.

Question 6

Explain NO signalling

Answer 6

• The target for NO signalling is guanylyl cyclase - Prod cGMP and causes multiple responses:
  1. cGMP-Dep protein kinase (PKG)
  2. Non-selective cation channels
  3. Dec in intracellular Ca2+
  4. PDE activity

Question 7

Describe NO signalling in CNS

Answer 7

Question 8

What happens in NO siganlling in the PNS?

Answer 8

• Nitroxidergic, cholinergic and VIPergic cotransmission

Question 9

How does NO neurotransmission effect different regions?

Answer 9

1. Brain
   * Many locations, high densities in cerebellum & accessory olfactory bulb
   * Linked to glutamatergic neurotransmission
   * Regulation of excitability, firing and long-term potentiation & depression, learning and memory, NT release and development
   * Excess levels of NO may be neurotoxic
2. Cerebral vessels
   * Vasodilator
3. Salivary glands
   * Vasodilator

Question 10

Where else is there NO neurotransmission?

Answer 10

• Myenteric neurons
• Pyloric sphincter
• Penis
• Urinary Bladder (Reg of outflow)
• Trachea (Bronchodilation)
• Rabbit portal vein (Vasorelaxation)

Question 11

What is NO cotransmission?

Answer 11

1. With VIP – myenteric neurones, the eyes, salivary glands, and cerebral arteries
2. With ACh – salivary glands
3. With ATP – rabbit portal vein
4. With CO – myenteric neurones
5. With glutamate – the cerebellum
6. With GABA – the cerebellum
7. With choline acetyltransferase – the brainstem
8. With somatostatin and NPY – the corpus striatum

Question 12

Explain NO modulation?

Answer 12

• NOS inhibitors suppress peptide outflow from parasympathetic nerves in salivary gland, pancreas & intestine
• NO donor enhanced & NOS inhibition reduced, basal release of ACh in brain

Question 13

What is CO?

Answer 13

• Stable neutral molecule
• Relatively long half-life
• Formed by heme oxygenase

Question 14

What are Heme Oxygenase?

Answer 14

• HO1 - Heat shock protein
• HO2 - Constitutive
• HO3 - Consitutive

Question 15

What are the actions of CO?

Answer 15

• Activates soluable guanylyl cyclase
• HO inhibitors
• Colocalised with nNOS in myenteric neurons
• Vas deferens

Question 16

What happens with NO in disease?

Answer 16

• NO reacts with superoxide to form peroxynitrite, which causes oxidative injury - stroke.
• Parkinson’s disease - Inc nitrotyrosine and accumulation and overexpression of nNOS in polymorphonuclear cells of PD patients