Nitric oxide and cyclic GMP Flashcards

1
Q

Explain Nitric Oxide ?

A
  • Produced in response to a variety of agents including acetylcholine, bradykinin, thrombin, Ca2+, excitatory amino acids, etc
  • Gas which diffuses rapidly through membranes allowing it to act as intracellular and extracellular messenger
  • Very reactive free radical which reacts with species containing unpaired electrons such as oxygen, superoxide, metal ions: half life of less than 10s: metabolised to nitrate and nitrite (inert)
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2
Q

Structure of Nitric Oxide Synthase ?

A
  • NO synthase - 2 distinct forms – constitutive and inducible
  • Constitutive
    -Endothelial NOS (eNOS) - found in endothelial cells and neurons
  • Neuronal NOS (nNOS) - found in neurons in CNS and skeletal muscle: Ca2+/calmodulin dependent: Produces pmoles of NO over short term (secs)
  • Inducible
    iNOS - involved in the immune system where it is induced to combat infections
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3
Q

Nitric Oxide is an example of paracrine signalling

A
  • Highly diffusible gas with very short half-life

- Signals to neighbouring cells (paracrine); non-hormonal

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4
Q

Outline of pathway from NO downstream ?

A
  • Nitric oxide can diffuse from a neighbouring cell, or be synthesised in the cell by NO synthase in response to e.g. Ca2+ downstream of hormonal signalling
  • The NO produced activates a soluble receptor (i.e. not membrane-bound) called soluble guanylate cyclase
  • This makes a second messenger called 5’3’cGMP (analogous to 3’5’cAMP)
  • cGMP activates its own effector molecule, a kinase called protein kinase G (PKG)
  • PKG phosphorylates downstream target proteins to achieve the outcome in the cell
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5
Q

Explain 3’5’cyclic GMP ? e.g. what it’s made and broken down by ?

A
  • Analogous to 3’5’ cAMP, but with a guanine nucleotide
  • Made by guanylate cyclase; broken down by cGMP phosphodiesterase
  • Intracellular concentration 10-100x less than that of cAMP
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6
Q

How are Guanylate Cyclase Receptors similar to adenylate cyclase ?

A

Like adenylate cyclase, guanylate cyclase has two catalytic domains that must be brought together for activity

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7
Q

However, Guanylate Cyclase Receptors unlike AC functions as ?

A

A dimer

- There are soluble (cytoplasmic) and particulate (membrane-bound) versions

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8
Q

Solubility of Guanylate Cyclase Receptors ?

A

Soluble has no ligand binding site but does have haem domain

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9
Q

Explain what group, what it’s linked to, activated by ?

A
  • No hormone binding site however has haem prosthetic group in the regulatory domains which interact with free radicals causing conformational change and activation
  • Linked to changes in intracellular Ca2+
  • Activated by nitroprusside and nitroglycerin which can liberate nitric oxide within tissues
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10
Q

Nitric oxide (NO) and other free radicals are major regulators of ?

A

Metabolism and cell function

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11
Q

Explain cGMP-stimulated Protein Kinase (PKG) ?

A
  • Exists as an antiparallel dimer of a single polypeptide chain
  • Catalytic site inhibited by N-terminal pseudosubstrate domain
  • Two cGMP binding sites per monomer: Binding cGMP causes release of pseudosubstrate from active site and activation of protein phosphorylation
  • Phosphorylates Arg-Arg-X-Ser motifs and therefore has similar substrates as cAMP-dependent protein kinase
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12
Q

What can cGMP also activate?

A

cGMP also:

  • Activates cGMP-activated ions channels increasing ion fluxes
  • Activates cGMP-regulated phosphodiesterase
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13
Q

Explain NO in action ?

A
  • A compound (nitrophorin) in the saliva of the kissing bug releases NO in the bloodstream after it bites a human host. This leads to vasodilation and an extended feeding period for the insect
  • (Note that histamine will bind to nitrophorin, inhibiting the anti-inflammatory response)
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14
Q

What can activation of PKG by cGMP lead to ?

A

To activation of myosin phosphatase which in turn leads to release of calcium from intracellular stores in smooth muscle cells. This in turn leads to relaxation of the smooth muscle cells

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15
Q

What is Nitroglycerin used for?

A

Nitroglycerin – used to relieve the chest pains experienced in angina where there is compromised blood flow in the heart

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16
Q

What does Nitroglycerin interact with, dilate ?

A
  • Interacts with tissue thiols to form nitrossothiols which spontaneously decompose to release NO
  • This dilates coronary arteries and improves circulation in the heart preventing anoxia and cellular damage
17
Q

NO/oxygen mix used as ?

A

A last-resort treatment for pulmonary hypertension in neonatal intensive care

18
Q

Sildenafil is a mimic of ?

A

CGMP

19
Q

So what does Sildenafil (Viagra) do ?

A

Autonomic nerves release NO causing production of cGMP and relaxation of the vascular smooth muscle cells in the erectile tissue of the penis

20
Q

Viagra is an inhibitor of ?

A

The cGMP phosphodiesterase and potentiates the action of NO by preventing the breakdown of cGMP prolonging the time an erection can be maintained