Nuclear receptors regulate gene expression by binding to ligands that pass through the cell membrane via simple diffusion. These receptors are located in the cytoplasm or nucleus and bind small molecule ligands like steroids, lipids, vitamins, and thyroid hormone to function as transcriptional coactivators. Nuclear receptor ligands come in various structures including steroids like estrogen, progesterone, and androgen as well as non-steroidal lipophilic hormones such as vitamin D, retinoic acid, fatty acids, and thyroid hormone. Some receptors have unknown ligands and are called "orphan" receptors. Steroid receptors differ from peptide receptors in their half-life, speed of action, duration of effect, location, and degree of post-receptor regulation

1. Nuclear Receptors
By: Dr. Vahid Nikoui
Email: nikoui@razi.tums.ac.ir

2.  Regulate gene expression
 Ligands pass the cell membrane by simple
diffusion
 Receptors in the cytoplasm or in the nucleus

3. Small molecule coactivators of transcription
Steroids

4. Small molecule coactivators of
transcription
Lipid-Soluble Vitamins & Thyroid Hormone
Vitamin A
Thyroid Hormone

5. Nuclear receptor ligands are structurally diverse
 Steroids
– Estrogen (ER α,β)
– Progesterone (PR)
– Androgen (AR)
 Non-steroidal lipophilic hormones
– 1, 25-(OH)2-vitamin D3 (VDR)
– All- trans-retinoic acid (RAR α,β, γ)
– 9-cis-retinoic acid (RXR α,β, γ)
– Fatty acids (PPAR α,β, γ)
– Thyroid hormone (TR α,β)
 Orphans (No ligand or ligand unknown)

6. Steroid hormone
receptors

7. Action of Steroid Hormones versus
Peptide Hormones
Peptide Hormones Steroids
Half-life in circulation short long
Speed of action fast slow
Duration of effect short long
Location of receptor membrane inside
Post-receptor regulation high low
Signal amplification high low

9. Steroid Receptor Action
Roles of Heat Shock Proteins and HREs
hsp90
hsp70
H
hsp70
H H
R
hsp56
dimerize
H H
P?
H H
Gene
Transcription HRE target gene
5’ flanking region

12. Nuclear hormone receptor: domain structure
Zinc finger
DNA binding
domain…
inserts into
major groove
of DNA

14. Role of Phosphorylation in Steroid Receptor Activation
8-bromo cyclic AMP
PKA?
+ Phosphate
hypervariable DBD HBD
transcription

15. HETERODIMERS
CONTAINING RXR

16. T3 HORMONE
VITAMIN D3
ALL-TRANS RETINOIC ACID
9-CIS RETINOIC ACID

19. Thyroid Hormone
Receptors

23. Thyroid hormone receptors

25. THANK YOU !