6 - Intracellular Receptors, NO Signalling - Gray Flashcards

1
Q

Describe the ligands for cell surface receptors and what they effect

A
  • hydrophilic
  • eg peptide hormones eg insulin OR charged molecules eg adrenaline (PICA)
  • affect enzyme activity and gene expression (fast acting)
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2
Q

describe the ligands for intracellular receptors, how they reach their receptors and where and give examples

A
  • often small hydrophobic molecules that can diffuse across plasma membranes and interact with their receptors in cytoplasm or nucleus
  • eg NO - interacts with its receptor which is an enzyme therefore directly affecting its activity (granulate cyclase)
  • steroid hormone receptor complexes- affecting transcription of genes through binding to enhancer regions
  • auxin sends TFs to be degraded
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3
Q

draw a diagram showing how NO enters the cell and interacts with its receptor

A
  • NO = dissolved gas that diffuses through membrane
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4
Q

what is the function of NO and what is the result of NO binding to guanylate cyclase (GC)?

A
  • NO causes relaxation of smooth muscle cells surround blood vessels, expand, increase of blood flow and reducing blood pressure
  • NO binding to GC causes activation of enzyme catalysis cGMP from GTP
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5
Q

what are the 2 main ways that GC can be activated?

A
  • activation of the membrane bound receptor with intracellular GC domain. binding of atrial naturetic peptide to extracellular domain
  • binding of NO to the soluble GC receptor found in cytoplasm
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6
Q

what is the result of cGMP presence?

A

activation of the cGMP-dependent protein kinase G

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7
Q

draw the structure of the GC receptor and explain its binding sites and how it is activated.

A
  • at low [NO] only one biding site occupied. binds to the high affinity haem group which stimulates low levels of catalytic activity
  • at higher [NO] both binding sites can be occupied -> higher levels of catalytic activity. activity increased few 100 fold
  • easily reversible as soon as [NO] drops
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8
Q

draw a diagram and explain how NO causes a drop in blood pressure

A
  • ACh released from blood vessel lumen interacts with GPCR on endothelial cell membrane
  • activation of ACh GPCR, activation of Gqa protein which activates PLC (B iso form)
  • PLC cleaves PIP2 -> IP3
  • causes release of intracellular Ca2+
  • Ca2+ binds to calmodulin to active Nitric oxide synthase
  • arginine + O2 -> citrulline + NO
  • NO = paracrine signal to nearby muscle cells. diffuses locally. short half life (2-30secs)
  • NO enters muscle cells and binds to guanylate cyclase R and activating it. GTP -> cGMP and PPi
  • cGMP activates PKG, drop in intracellular Ca
  • relaxation of muscle cell
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9
Q

draw a diagram (showing the enzymes etc) and explain outline how smooth muscle cells contract and relax

A
  • myosin light chain kinase activation involves Ca and Calmodulin (CaM) binding
  • results in P of the myosin light chain causing relocation of the myosin head
  • activation of a MLC phosphatase (by PKG activity) and a reduction in intracellular Ca2+ and IP3 (also through PKG inhibiting Ca channels) meaning MLCK inactive causes deP of the MLC -> relaxation
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10
Q

how does phosphodiesterase link to smooth muscle cell contraction and NO signalling? name the specific PDE invovled in this

A
  • PDE5
  • PDE converts cGMP -> GMP therefore inactivation of PKG
  • therefore we get contraction of SMC
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11
Q

what is the result (in terms of bodily function) of NO release?

A

NO release by nerve terminals in penis responsible for local blood vessel dilation in penis

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12
Q

how can erectile dysfunction be treated?

A

sildenafil citrate is a reversible inhibitor of PDE5 that prevents cGMP hydrolysis so blood vessels can remain dilated and blood flow occurs

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13
Q

describe 2 other NO signalling pathways

A
  • oxygen depravation at high altitude can cause NO signalling to cause blood vessel dilation -> increased blood flow therefore more O2 to muscles
  • HDL cholesterol stimulates NO production. blood vessel dilation helping to prevent ischaemia and angina
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14
Q

describe 2 conditions that viagra can be used to treat

A
  • cardiac hypertrophy
  • pulmonary hypertension
    both invovle high blood pressure. in heart this can cause thickening of the heart walls (bad)
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15
Q

describe the discovery of NO signalling (Nobel prize - 1998)

A
  • ACh applied to blood vessels. showed variation in responses (sometimes dilated/constricted). dependent upon whether endothelium layer was present. showed that signal released from endothelium
  • showed that the endothelium relaxation factor showed the same spectral shift as NO when added to haemoglobin
  • showed that nitroglycerine response to relate SMC via GC invovled NO release
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