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Nuclear Receptors and Their Signaling Pathway



Nuclear Receptors

  • Located inside the cell.

    • This is in contrast to other types of receptors which are located on the cell membrane.

  • Their ligands are lipid-soluble ⟶ Can cross the lipid bilayer ⟶ Bind the receptor located inside the cell.

  • Are transcription factors ⟶ Regulate gene expression and protein synthesis.

  • Two main subfamilies:

    • Receptors for steroid hormones e.g. glucocorticoids, mineralocorticoids, androgens, estrogens.

    • Receptors for vitamin D, thyroid hormones, and retinoic acid

    • Other nuclear receptors recognize a wide range of xenobiotics and metabolites.

Location During Resting Condition

  • Cytoplasm:

    • Glucocorticoid receptor

    • Mineralocorticoid receptor

  • Nucleus:

    • Estrogen receptor

    • Progesterone receptor

  • Bound to DNA:

    • Thyroid hormone receptor

    • Retinoic acid receptor

Structure

  • Ligand Binding Domain

    • Binds with ligand.

  • DNA Binding Domain

    • Binds with DNA.

  • Transactivation Domain

    • Brings about changes in DNA conformation ⟶ Initiate transcription.


Signaling Pathway for Glucocorticoid Receptor

Resting Condition

  • Receptor is located in the cytoplasm

  • Receptor is inherently capable of binding with the respective gene. But under resting condition, their activity is prevented by a chaperone protein like Heat Shock Protein-90 (HSP-90)

Activation and Signaling

Ligand binds with the ligand-binding Domain

↓

Release of HSP-90

↓

Two receptors dimerize and get activated

↓

The pair enters the nucleus

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Binds to a specific region of the gene called Glucocorticoid Responsive Element (GRE)

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Fassilitation or suppresion of gene expression

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In case of facilitation, mRNA is produced

↓

mRNA goes to the cytoplasm

↓

Translated into protein

↓

Protein brings about changes in cellular activity


Effect develops slowly but lasts longer:

Protein synthesis takes time

↓

Effect of nuclear receptors take longer to appear

↓

Synthesized proteins work for a while even when the stimulus is removed

↓

Effect of nuclear receptors takes longer to disappear

 

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