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
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Release of HSP-90
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Two receptors dimerize and get activated
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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
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mRNA goes to the cytoplasm
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Translated into protein
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Protein brings about changes in cellular activity
Effect develops slowly but lasts longer:
Protein synthesis takes time
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Effect of nuclear receptors take longer to appear
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Synthesized proteins work for a while even when the stimulus is removed
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Effect of nuclear receptors takes longer to disappear