Objectives Section 3 Nuclear Receptors 1 Define Nuclear

Objectives Section 3: Nuclear Receptors 1. Define Nuclear Receptor – receptors as transcriptional regulators. Outline nuclear receptor classifications Describe basic nuclear receptor structure 2. Define HRE: hormone response element and how they function 3. Describe nuclear receptor binding domain 4. Describe ‘cytosolic’ steroid receptors Estrogen receptors, and other similar family members, GR, MR, PR, AR Describe the process of ligand mediated nuclear translocation 5. Describe ‘nuclear’ hormone receptors Thyroid hormone receptors, and other similar family members, RAR, PPAR, VDR Describe the process of receptor heterodimerization with RXR 6. Describe non-genomic steroid/hormone receptors Estrogen receptors, GPR 30 Thyroid hormone receptors

Nuclear Receptors: 1. 2. 3. 4. 5.

Nuclear Receptor Families 1. Thyroid hormone Family Receptor Ligand 2. Retinoid-X-Receptor Family Receptor Ligand Thyroid hormone receptor TRa TRb Thyroid hormone Hepatocyte nuclear factor -4 HNF 4 a NHF 4 g Fatty acids Retinoic acid receptor RARa RARb RARg Vitamin A Retinoid-X receptor RXRa RXRb RXRg Retinoids (9 -cis-retinoic acid) Peroxisome proliferator -activated receptor PPARa PPARb/d PPARg Fatty acids Prostaglandins Testicular receptor TR 2 TR 4 Rev. Erb. Aa Rev. Erb. Ab heme TLX (drosophila) PNR (photoreceptor nuclear receptor) TLX PNR RAR-related orphan receptor RORa RORb RORg Cholesterol, ATRA COUP(Chic ovalbumin upstream prom TF 1) EAR (v-erb. A related) COUPTFII EAR 2 Liver X-receptor like LXRa LXRb FXRb Oxysterols Vit D-receptor like (Pregnane rec) (Const androstane rec) VDR PXR CAR Vitamin D Xenobiotics Androstane NR w/ 2 binding domains 2 DBD-NRa 2 DBD-NRb 2 DBD-NRg (farnesoid receptors) Bile acids

Nuclear Receptor Families 3. Estrogen Family Receptor Ligand 4. Nerve Growth Factor IB Receptor Estrogen receptor ERa ERb Estrogen Nerve growth factor IB Nuclear receptor related 1 Neuron-derived orphan receptor NGF 1 B NURR 1 NOR 1 Estrogen related receptor ERRa ERRb ERRg 3 -Ketosteroids Gluccocorticoid Mineralocorticoid Progesterone Androgen GR MR PR AR Cortisol Aldosterone Progesterone Testosterone 5. Steroidogenic Factor Liver receptor homolog-1 6. Germ cell nuclear factor SF 1 LRH-1 Phosphotidylinositols Germ cell nuclear factor GCNF Ligand

Nuclear Receptor Structure Domains A/B: C: D: E: F:

Steroid Receptor Function (Estrogen Receptor) Steroid Hormone Receptor Signaling 1. 2. 3. 4.

Nuclear Receptor Function (Thyroid Hormone Receptor) Nuclear Hormone Receptor Signaling 1. 2. 3. 4.

Ligand Binding Domain Function ix hel Ligand Binding Domain 1. 4 helix 12 2. Glu LXXLL ix hel 3 Lys 3. 4. 5.

Hormone Response Elements (HRE) Rule of 5 for non-steroidal nuclear receptors RXR/PPAR +1 RAR +2 RXR + VDR +3 TR

Estrogen Receptor Signaling Estrogen Receptor Function 1. 2. 3. 4. Genomic Signaling 1. 2. 3. 4. Non-genomic signaling 1. 2.

Thyroid Hormone Receptor Signaling Thyroid Hormone Receptor Function 1. 2. 3. 4. Genomic Signaling 1. 2. 3. 4. Non-genomic signaling Sinha RA. 2014: Trends Endocrinol Metab 25: 538.