Nuclear Receptors (2023-24) PDF

WEEK 31 MPharm Programme Receptor Superfamilies Nuclear Receptors Dr Gabriel Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK Receptor Superfamilies 31 Receptor Superfamily A group of receptors with a similar basic...

WEEK 31 MPharm Programme Receptor Superfamilies Nuclear Receptors Dr Gabriel Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK Receptor Superfamilies 31 Receptor Superfamily A group of receptors with a similar basic molecular structure and that use the same signal transduction pathway 4 Major Receptor Superfamilies Ligand-gated / Ion channel linked receptors G-protein-coupled receptors Kinase-linked receptors Intracellular / Nuclear receptors Slide 2 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Receptor Superfamilies  Slide 3 of 29 MPharm  PHA112  Receptor Superfamilies – Nuclear Receptors WEEK Outline of Lecture 31 Introduction to the nuclear receptor superfamily Basic molecular structure of nuclear receptors Subclassification of nuclear receptors Activation mechanism and signalling pathways of Class I/Type I (steroid/nuclear hormone) nuclear receptors Activation mechanism and signalling pathways of Class II/Type II nuclear receptors (RXR heterodimers) The role of nuclear receptor signalling in health and disease Slide 4 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors Learning Outcomes WEEK 31 At the end of this lecture, you should be able to: Describe the key features/characteristics of the nuclear receptor superfamily Describe the subclassification of nuclear receptors Describe the activation mechanism & signalling pathways of Class I/Type I nuclear receptors Describe the activation mechanism & signalling pathways of Class II/Type II nuclear receptors Appreciate the role of nuclear receptor signalling in health and disease Slide 5 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK Nuclear Receptors (NRs) 31 A superfamily of intracellular DNA-binding transcription factors that selectively bind small-molecule lipophilic ligands, and transduce their signals into specific changes in gene expression They are located intracellularly (in the cytosol or nucleus) and translocate to the nucleus upon ligand binding  recognise & bind specific DNA element sequences in the regulatory regions of their target gene  control of the transcription of target genes The human NR superfamily consists of 48 members, including receptors for steroid hormones, thyroid hormone, vitamin A, vitamin D, fatty acids & cholesterol metabolites (oxysterols) They serve as on-off switches for genes which regulate cell differentiation, proliferation, and metabolism and, thus, play key roles in the pathology of cancer, cardiovascular & endocrine diseases, inflammation, infertility, etc Slide 6 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Slide 7 of 29 Nuclear Receptor Signalling MPharm PHA112 Receptor Superfamilies – Nuclear Receptors Structure Nuclear Receptors (NRs) WEEK 31 NRs are monomeric proteins that share a common structural architecture consisting of 5 main domains: N-terminal (A/B) domain (NTD) – harbours a ligand-independent transcriptional activation function-1 site (AF-1) DNA-binding (C) domain (DBD) – mediates DNA recognition & receptor binding; comprises 2 ‘zinc finger’ motifs – each containing a zinc ion tetrahedrally coordinating 4 cysteine residues Hinge (D) region – highly flexible; links the DBD to LBD; also plays a role in receptor dimerization Ligand-binding (E) domain (LBD) – harbours a ligand-binding site or pocket & a ligand-dependent transcriptional activation function-2 site (AF-2) that modulates co-activator & co-repressor binding C-terminal (F) domain – harbours motifs with nuclear localisation signals & binding sites for accessory heat shock & other proteins Slide 8 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Slide 9 of 29 Structure of Nuclear Receptors (NRs) MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Structure of Nuclear Receptors (NRs) Slide 10 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Classification of Nuclear Receptors (NRs) NR superfamily members divided into 2 main groups depending on the identification of endogenous ligands: Endocrine NRs – endogenous ligands have been identified Orphan NRs – endogenous ligands remain unknown NR superfamily members further subclassified into 4 classes, based on dimerization, DNA binding motifs & ligand specificity Class I (Steroid Receptors/Nuclear Hormone Receptors) – endocrine NRs that bind to specific DNA elements as homo-dimers Class II (RXR Heterodimers) – endocrine NRs that bind to specific DNA elements as hetero-dimers with the retinoid X receptor (RXR) Class III (Dimeric Orphan Receptors) – orphan NRs that bind to specific DNA elements as homo- and heterodimers Class IV (Monomeric Orphan Receptors) – orphan NRs that bind to specific DNA elements as monomers Slide 11 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Classical Nuclear Receptor Superfamily Slide 12 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Classical Nuclear Receptor Superfamily Slide 13 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Classical Nuclear Receptor Superfamily Slide 14 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors Class I Nuclear Receptors WEEK 31 Steroid Receptors/Nuclear Hormone Receptors Comprise receptors for the steroid hormones – oestrogen (ER), progesterone (PR), androgens/testosterone (AR), glucocorticoids/ cortisol (GR) & mineralocorticoids/aldosterone (MR) Typically located in the cytoplasm as monomers bound to chaperone proteins, e.g. HSP70 and HSP90, etc Binding of steroid hormone  conformational change  receptor activation via dissociation from chaperone proteins  exposure of the nuclear localization sequence Next, the activated receptors homo-dimerize  translocate to the nucleus  recruit co-regulators (co-activators or co-repressors) Binding to specific hormone response element (HRE) on DNA  transactivation or transrepression of target genes Slide 15 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Slide 16 of 29 Class I Nuclear Receptor Signalling MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Slide 17 of 29 Class I Nuclear Receptor Signalling MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 NR-mediated Activation or Repression of Target Genes Slide 18 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 NR-mediated Activation or Repression of Target Genes Slide 19 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors Class II Nuclear Receptors WEEK 31 RXR Heterodimers A large subfamily of NRs comprising: Receptors for thyroid hormones (TR), vitamin A metabolites (RARs & RXRs) & vitamin D (VDR) ‘Metabolic receptors’ – receptors for fatty acids (PPARs), bile acids (FXR) & cholesterol metabolites or oxysterols (LXRs) Act as ‘metabolic sensors’ that finely tune the amount of key metabolic products (cholesterol & fatty acids) via regulation of enzymes responsible of their biosynthesis and/or degradation Receptors for xenobiotics – the pregnane X receptor (PXR) & the constitutive androstane receptor (CAR) Specialized receptors for interacting with xenobiotics – promote the degradation of potentially toxic compounds via activation of hepatic metabolizing cytochrome P450 enzymes Slide 20 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors Class II Nuclear Receptors WEEK 31 Name Abbreviation Canonical Ligands Thyroid hormone receptors (, ) TR, TR Triiodothyronine (T3), Thyroxine (T4) Vitamin D receptor VDR 1, 25-dihydroxyvitamin D3, lithocholic acid Retinoic acid receptors (α, , ) RAR, RAR, RAR Vitamin A (All-trans retinoic acid, 9-cis retinoic acid) Retinoid X receptors (α, , ) RXR, RXR, RXR 9-cis retinoic acid Peroxisome proliferatoractivated receptor (α, , ) PPAR, PPAR, PPAR Fatty acids, prostaglandin leukotriene Liver X receptors (, ) LXR, LXR Oxysterols Farnesoid X receptor FXR Bile acids Pregnane X receptor PXR Xenobiotics Constitutive androstane receptor CAR Androstane, xenobiotics Slide 21 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK Class II Nuclear Receptor Signalling 31 Typically reside in the nucleus as heterodimer with the retinoid X receptor (RXR) Heterodimers are bound to specific DNA response elements even in the absence of their ligands Bound heterodimer recruits co-repressor complexes (NCoR & SMRT) with histone deacetylase (HDAC), and behave as active transcriptional repressors in the absence of their ligands Ligand binding  conformational change  release of co-repressor complexes & recruitment of co-activators with histone acetyltransferase (HAT)  transactivation of target genes Some heterodimers (TR-RXR, VDR-RXR) require binding of ligands for both partners for activation (‘non-permissive’ complexes) Other heterodimers (PPAR-RXR, LXR-RXR) only require binding of ligand for either partner for activation (‘permissive’ complexes) Slide 22 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Class II Nuclear Receptor Signalling Generalised Scheme Slide 23 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 Class II Nuclear Receptor Signalling Thyroid Hormone Receptor Thyroid Hormone Transporter Slide 24 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK Nuclear Receptors in Health & Disease 31 Class I NRs play unique roles in the maintenance of cellular homeostasis, regulation of gene expression in embryogenesis & tissue development Class II NRs play an important role in many cellular functions including lipid metabolism, cell proliferation, differentiation, adipogenesis & inflammatory signalling Dysregulation, e.g. mutations, misfolding, or alteration of signaling pathways, can lead to systemic organ dysfunction and disease, including inflammation, cancer, diabetes, cardiovascular disease, obesity and reproductive disorders Slide 25 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK Nuclear Receptors in Health & Disease 31 The Androgen Receptor (AR) essential for male sexual differentiation, bone growth, muscle homeostasis & development dysregulation is associated with pathogenesis of primary prostate cancer The Progesterone Receptor (PR) plays critical role in the development of mammary glands & other female reproductive organs dysregulation is associated with prostate cancer progression The Oestrogen Receptor (ER) plays a key role in female reproduction and in the development & function of secondary sexual characteristics dysregulation is associated with breast cancer development & metastasis Slide 26 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors Nuclear Receptors in Health & Disease WEEK 31 The Retinoid X Receptors (RXRs) play a role in lipid metabolism, apoptosis & the immune system downregulation or loss of RXR signaling has been shown to promote inflammation of vital organ systems, e.g. the liver RXR overexpression associated with cell growth reduction or increased susceptibility to apoptosis in prostate cancer cells The Peroxisome Proliferator-Activated Receptors (PPARs) involved in several physiological processes including modulation of cellular differentiation, development & metabolism Ligands of PPAR, e.g. gemfibrozil and clofibrate, are clinically effective at  TG & LDL and  HDL Ligands of PPAR, e.g. thiazolidinediones (rosiglitazone & pioglitazone), enhance peripheral insulin sensitivity & are used in the treatment Type II diabetes Slide 27 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors WEEK 31 NR-Targeted Drugs Approved for Cancer Drug Mode of Action Tamoxifen SERM Treatment of metastatic breast cancer; reduction in the risk of breast cancer Toremifene SERM Treatment of metastatic breast cancer Raloxifene SERM Reduction in the risk of breast cancer Fulvestrant SERD Treatment of metastatic breast cancer Flutamide AR antagonist Treatment of metastatic prostate cancer Bicalutamide AR antagonist Treatment of metastatic prostate cancer Enzalutamide AR antagonist Treatment of mCRPC Apalutamide AR antagonist Treatment of non-metastatic CRPC Tretinoin (all-transRAR agonist retinoic acid) Alitretinoin (9-cis- RAR and RXR agonist retinoic acid) Bexarotene Slide 28 of 29 RXR modulator MPharm PHA112 Approved Indications Treatment of APL Treatment of cutaneous lesions in patients with AIDS-related Kaposi sarcoma Treatment of CTCL Receptor Superfamilies – Nuclear Receptors WEEK Recommended Reading 31 Katzung BG, Vanderah TW. Basic & Clinical Pharmacology, 15th Edition. New York: McGraw-Hill Education, 2021. ISBN: 978-1260452310. Ritter JM et al. Rang and Dale’s Pharmacology, 9th Edition. London: Elsevier, 2019. ISBN: 978-0702074486. Slide 29 of 29 MPharm PHA112 Receptor Superfamilies – Nuclear Receptors