Week 34 / Nuclear Receptors Flashcards
Q: What is a receptor superfamily?
A: A receptor superfamily is a group of receptors with a similar basic molecular structure that use the same signal transduction pathway.
Q: What are the four major receptor superfamilies?
A:
Ligand-gated / Ion channel-linked receptors
G-protein-coupled receptors
Kinase-linked receptors
Intracellular / Nuclear receptors
Q: What are nuclear receptors (NRs)?
A: Nuclear receptors (NRs) are a superfamily of intracellular DNA-binding transcription factors that bind small-molecule lipophilic ligands and transduce their signals to cause changes in gene expression.
Q: Where are nuclear receptors located and what happens upon ligand binding?
A: Nuclear receptors are located intracellularly (in the cytosol or nucleus) and translocate to the nucleus upon ligand binding, where they recognize and bind specific DNA sequences in the regulatory regions of their target genes to control gene transcription.
Q: How many members are in the human nuclear receptor superfamily, and what types of receptors does it include?
A: The human nuclear receptor superfamily consists of 48 members, including receptors for steroid hormones, thyroid hormone, vitamin A, vitamin D, fatty acids, and cholesterol metabolites (oxysterols).
Q: What roles do nuclear receptors play in the body?
A: Nuclear receptors serve as on-off switches for genes that regulate cell differentiation, proliferation, and metabolism, playing key roles in diseases such as cancer, cardiovascular and endocrine diseases, inflammation, and infertility.
Q: What are the five main domains of nuclear receptors (NRs)?
A: The five main domains of nuclear receptors are:
N-terminal (A/B) domain (NTD) - Contains a ligand-independent transcriptional activation function-1 site (AF-1).
DNA-binding (C) domain (DBD) - Mediates DNA recognition and receptor binding; includes two ‘zinc finger’ motifs with zinc ions coordinating cysteine residues.
Hinge (D) region - Highly flexible, links the DNA-binding domain (DBD) to the ligand-binding domain (LBD), and plays a role in receptor dimerization.
Ligand-binding (E) domain (LBD) - Contains the ligand-binding site and transcriptional activation function-2 site (AF-2), modulating co-activator and co-repressor binding.
C-terminal (F) domain - Contains nuclear localization signals and binding sites for accessory proteins like heat shock proteins.
Q: How are nuclear receptors (NRs) classified?
A: Nuclear receptors (NRs) are classified into two main groups based on the identification of endogenous ligands:
Endocrine NRs - Endogenous ligands have been identified.
Orphan NRs - Endogenous ligands remain unknown.
They are further subclassified into four classes based on dimerization, DNA binding motifs, and ligand specificity:
Class I (Steroid Receptors/Nuclear Hormone Receptors) - Endocrine NRs that bind as homo-dimers to specific DNA elements.
Class II (RXR Heterodimers) - Endocrine NRs that bind as hetero-dimers with the retinoid X receptor (RXR) to specific DNA elements.
Class III (Dimeric Orphan Receptors) - Orphan NRs that bind as homo- and heterodimers to specific DNA elements.
Class IV (Monomeric Orphan Receptors) - Orphan NRs that bind as monomers to specific DNA elements.
Q: What are Class I Nuclear Receptors and how do they function?
A:
Class I Nuclear Receptors (Steroid Receptors/Nuclear Hormone Receptors) include receptors for steroid hormones like:
Estrogen (ER)
Progesterone (PR)
Androgens/Testosterone (AR)
Glucocorticoid/Cortisol (GR)
Mineralocorticoid/Aldosterone (MR)
Function:
Located in the cytoplasm as monomers bound to chaperone proteins (e.g., HSP70, HSP90).
Ligand (hormone) binding causes conformational change → dissociation from chaperones → exposes nuclear localization sequence.
The receptor homo-dimerizes and translocates to the nucleus.
It recruits co-regulators (co-activators or co-repressors).
Binds to a specific hormone response element (HRE) on DNA.
Leads to transactivation or transrepression of target genes.
Q: What are Class II Nuclear Receptors (RXR Heterodimers) and what are their roles?
A:
Class II Nuclear Receptors are RXR heterodimers, meaning they bind DNA as heterodimers with the Retinoid X Receptor (RXR). They are located in the nucleus even before ligand binding.
They include:
Receptors for thyroid hormones (TR), vitamin A (RARs & RXRs), and vitamin D (VDR)
Metabolic receptors:
PPARs (fatty acids)
FXR (bile acids)
LXRs (cholesterol metabolites/oxysterols)
→ Act as metabolic sensors, regulating biosynthesis & degradation of cholesterol and fatty acids.
Xenobiotic receptors:
PXR (Pregnane X Receptor)
CAR (Constitutive Androstane Receptor)
→ Promote detoxification of xenobiotics via activation of cytochrome P450 enzymes in the liver.
Q: How does Class II Nuclear Receptor (RXR Heterodimer) signalling work?
A:
Location: Already reside in the nucleus as heterodimers with RXR
DNA Binding: Bound to DNA response elements even without ligands
Without ligand:
Recruit co-repressors (NCoR & SMRT)
Recruit HDAC → Repress transcription
With ligand:
Causes conformational change
Releases co-repressors, recruits co-activators (with HAT) → Activates transcription
Permissiveness:
Non-permissive: Both partners (e.g., TR-RXR, VDR-RXR) must bind ligands for activation
Permissive: Only one partner (e.g., PPAR-RXR, LXR-RXR) needs to bind ligand for activation
Q: What roles do Nuclear Receptors (NRs) play in health and disease?
A:
Class I NRs:
Regulate cellular homeostasis, gene expression, embryogenesis, and tissue development
Class II NRs:
Involved in lipid metabolism, cell proliferation, differentiation, adipogenesis, and inflammatory signalling
Dysregulation (e.g., mutations, misfolding, altered signalling) can lead to:
Inflammation
Cancer
Diabetes
Cardiovascular disease
Obesity
Reproductive disorders
Q: What is the function of the Androgen Receptor (AR) and its link to disease?
A:
Essential for male sexual differentiation, bone growth, muscle homeostasis, and development
Dysregulation is associated with primary prostate cancer
Q: What role does the Progesterone Receptor (PR) play in health and disease?
A:
Critical for mammary gland and female reproductive organ development
Dysregulation is linked to prostate cancer progression
Q: What is the function of the Oestrogen Receptor (ER) and its disease association?
A:
Regulates female reproduction and secondary sexual characteristics
Dysregulation is associated with breast cancer development and metastasis
Q: What functions are associated with the Retinoid X Receptors (RXRs), and what happens when they’re dysregulated?
A:
Roles in lipid metabolism, apoptosis, and the immune system
Downregulation/loss promotes inflammation, especially in the liver
RXRα overexpression may lead to cell growth reduction or apoptosis susceptibility in prostate cancer cells
Q: What are the physiological roles of Peroxisome Proliferator-Activated Receptors (PPARs)?
A:
Involved in cell differentiation, development, and metabolism
Q: Name drugs targeting PPARs and their clinical uses.
A:
PPARα ligands (e.g., gemfibrozil, clofibrate): lower VLDL, triglycerides, and raise HDL
PPARγ ligands (e.g., rosiglitazone, pioglitazone): improve insulin sensitivity in Type II diabetes
