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Pharmacology: Nuclear Receptors and Drug Response
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Pharmacology: Nuclear Receptors and Drug Response

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Questions and Answers

What is the dimerization pattern of Class II Nuclear Receptors?

  • Homo- or heterodimer
  • Heterodimer with RXR (correct)
  • Monomer
  • Homodimer

    • Steroid hormone nuclear receptors bind to inverted repeat response elements.

    True

    What is the typical location of nuclear receptors that are not bound to ligands?

    Cytoplasm

    The direct repeat response element typically has a _______ base pair spacer.

    <p>0-5</p> Signup and view all the answers

    Match the following types of nuclear receptors with their characteristic ligands:

    <p>Steroid hormone NR = Glucocorticoid, estrogen RXR heterodimer = Fatty acids, retinoic acids, cholesterol Dimeric orphan NR = Unknown Monomeric orphan NR = Unknown</p> Signup and view all the answers

    What is the response element pattern for Class I Nuclear Receptors?

    <p>Inverted repeat</p> Signup and view all the answers

    Monomeric orphan nuclear receptors display constitutive activity.

    <p>True</p> Signup and view all the answers

    What is the function of the first zinc finger in the DNA binding domain of a nuclear receptor?

    <p>Recognition of specific hormone response elements (HREs)</p> Signup and view all the answers

    The N-terminal domain of a nuclear receptor is highly conserved.

    <p>False</p> Signup and view all the answers

    What is the function of the activation function 1 (AF1) in a nuclear receptor?

    <p>binds co-regulators in a ligand-independent manner</p> Signup and view all the answers

    The two zinc fingers in the DNA binding domain of a nuclear receptor are formed by __________ loops.

    <p>cysteine-rich</p> Signup and view all the answers

    Match the following parts of a nuclear receptor with their functions:

    <p>N-terminal domain = least conserved DBD (DNA binding domain) = Responsible for DNA recognition and binding Activation function 1 (AF1) = Binds co-regulators in a ligand-independent manner</p> Signup and view all the answers

    What is the common number of base pairs in the spacer region of a nuclear receptor response element?

    <p>3</p> Signup and view all the answers

    The second zinc finger in the DNA binding domain of a nuclear receptor is involved in receptor dimerization.

    <p>True</p> Signup and view all the answers

    What is the function of nuclear receptors after binding a ligand intracellularly?

    <p>binds to specific DNA sequences called hormone response elements (HREs) within the regulatory regions of target genes.</p> Signup and view all the answers

    Retinoid X receptor (RXR) forms homodimers to activate gene transcription.

    <p>False</p> Signup and view all the answers

    What are the two xenobiotic receptors mentioned in the text that are involved in the regulation of CYP expression?

    <p>pregnane X receptor (PXR) and constitutive androstane receptor (CAR)</p> Signup and view all the answers

    Nuclear receptors are classified into ______________________ subfamilies.

    <p>seven</p> Signup and view all the answers

    Match the following nuclear receptors with their functions:

    <p>PXR = Regulate xenobiotic metabolism CAR = Form heterodimers with RXR</p> Signup and view all the answers

    Cofactors are required for the interaction of nuclear receptors with DNA.

    <p>True</p> Signup and view all the answers

    What is the result of xenobiotics binding to xenobiotic receptors?

    <p>Increased CYP expression</p> Signup and view all the answers

    What is the main function of glucocorticoids (GCs)?

    <p>To regulate metabolic and immune responses</p> Signup and view all the answers

    The glucocorticoid receptor (GR) is a type of transcription factor.

    <p>True</p> Signup and view all the answers

    What is the result of ligand binding to the glucocorticoid receptor?

    <p>GR dissociates from the complex and exposes nuclear localisation signals</p> Signup and view all the answers

    The glucocorticoid receptor binds to the ______ response element (GRE) to increase gene transcription.

    <p>GGAACAnnnTGTTCT</p> Signup and view all the answers

    Match the following peroxisome proliferator-activated receptors (PPARs) with their primary functions:

    <p>PPARa = Fatty acid oxidation PPARb/d = Fatty acid oxidation PPARg = Adipogenesis, lipid metabolism, and insulin sensitivity</p> Signup and view all the answers

    What is the effect of GR binding to negative GRE?

    <p>Decrease in gene transcription</p> Signup and view all the answers

    The glucocorticoid receptor can bind to DNA as a monomer.

    <p>False</p> Signup and view all the answers

    The glucocorticoid receptor interacts with ______ to inhibit gene transcription.

    <p>activator protein 1 (AP1) and nuclear factor κB (NF-κB)</p> Signup and view all the answers

    What is the difference between non-permissive and permissive RXR heterodimers?

    <p>Non-permissive RXR heterodimers are activated by ligands of the partner NR, while permissive RXR heterodimers are activated by ligands of either NR or RXR, and synergistic effects occur when both NRs are activated</p> Signup and view all the answers

    What is the result of chronic use of glucocorticoids?

    <p>Adrenal suppression</p> Signup and view all the answers

    Glucocorticoids are involved in immune system enhancement.

    <p>False</p> Signup and view all the answers

    What is the role of the hinge region in the glucocorticoid receptor?

    <p>Overlaps with NLS1 and DBD</p> Signup and view all the answers

    The glucocorticoid receptor is encoded by the NR3C1 gene through ______________________.

    <p>alternative splicing of exon 9</p> Signup and view all the answers

    What happens to the glucocorticoid receptor upon ligand binding?

    <p>It dissociates from the complex with HSP90</p> Signup and view all the answers

    Match the following domains of the glucocorticoid receptor with their functions:

    <p>N-terminal domain = sites for post-translational modifications DNA-binding domain = binds to DNA response elements Hinge region = overlaps with NLS1 and DBD Ligand-binding domain = binds to glucocorticoids</p> Signup and view all the answers

    Glucocorticoids are involved in maintaining homeostasis and responding to stress.

    <p>True</p> Signup and view all the answers

    What is the ligand for Steroid NR?

    <p>Glucocorticoid, estrogen</p> Signup and view all the answers

    Nuclear receptors undergo dimerisation.

    <p>True</p> Signup and view all the answers

    What is the response element pattern for Steroid NR?

    <p>Inverted repeat (IR)</p> Signup and view all the answers

    RXR forms a ______________ with other nuclear receptors.

    <p>heterodimer</p> Signup and view all the answers

    What is the location of RXR?

    <p>Both nucleus and cytoplasm</p> Signup and view all the answers

    Match the following nuclear receptors with their characteristic ligands:

    <p>Steroid NR = Glucocorticoid, estrogen RXR = Fatty acids, retinoic acids, cholesterol PXR = Xenobiotics CAR = Xenobiotics</p> Signup and view all the answers

    What are the two xenobiotic receptors mentioned in the text?

    <p>PXR, CAR</p> Signup and view all the answers

    What is the characteristic of a Non-permissive RXR heterodimer?

    <p>Can only be activated by the ligand for the non-RXR partner</p> Signup and view all the answers

    PPARy can be activated without ligand in normal circumstances.

    <p>False</p> Signup and view all the answers

    What is the function of PPARy in adipocyte differentiation and mature adipocyte function?

    <p>Lipid metabolism, Glucose homeostasis</p> Signup and view all the answers

    PPARy forms a ______________ with RXR.

    <p>heterodimer</p> Signup and view all the answers

    Match the following PPARs with their primary functions:

    <p>PPARa = Fatty acid oxidation PPARb/delta = Ubiquitous expression - FA oxidation PPARy = Adipocyte differentiation and mature adipocyte function</p> Signup and view all the answers

    FGF1 blocks _______ of PPARy.

    <p>SUMOylation</p> Signup and view all the answers

    RXR forms homodimers to activate gene transcription.

    <p>False</p> Signup and view all the answers

    What is the role of the first zinc finger in the DNA binding domain of a nuclear receptor?

    <p>Recognizes specific hormone response elements</p> Signup and view all the answers

    The hinge region in nuclear receptors is highly conserved

    <p>False</p> Signup and view all the answers

    What is the function of helix 12 in the ligand binding domain of a nuclear receptor?

    <p>Important role in co-activator/repressor switching</p> Signup and view all the answers

    The ligand binding domain (LBD) of a nuclear receptor forms a ______ pocket formed by 2 α-helices

    <p>hydrophobic</p> Signup and view all the answers

    Match the following regions of a nuclear receptor with their functions:

    <p>DBD = Responsible for DNA recognition and binding Hinge Region = Links DBD and LBD, contains nuclear localization signal (NLS) LBD = Forms a hydrophobic pocket, binds ligand, and recruits co-regulators</p> Signup and view all the answers

    What is the function of Activation Function 2 (AF2) in a nuclear receptor?

    <p>Binds co-regulators in a ligand-dependent manner</p> Signup and view all the answers

    Post-translational modifications occur in the ligand binding domain of a nuclear receptor

    <p>True</p> Signup and view all the answers

    The second zinc finger in the DNA binding domain of a nuclear receptor is involved in ______

    <p>receptor dimerization</p> Signup and view all the answers

    What is the function of the hinge region in allowing flexibility for conformational change after ligand binding?

    <p>It allows flexibility for conformational change after ligand binding</p> Signup and view all the answers

    Study Notes

    Nuclear Receptors

    • 48 nuclear receptors (NRs) are ligand-activated transcription factors that bind a ligand intracellularly and interact with DNA directly via recognition of response elements
    • Classified into seven subfamilies

    Classification of Nuclear Receptors

    • Steroid Hormone NRs: e.g., glucocorticoid, estrogen; ligand; receptor homodimer; response element: inverted repeat (IR) or direct repeat (DR)
    • RXR Heterodimers: e.g., fatty acids, retinoic acids, cholesterol; ligand; receptor heterodimer; response element: direct repeat (DR)
    • Dimeric Orphan NRs: unknown ligand; receptor homo- or hetero-dimer; response element: direct repeat (DR)
    • Monomeric Orphan NRs: unknown ligand; receptor monomer; response element: binds to one extended response element half-site

    Structure of a Nuclear Receptor

    • N-terminal Domain (A/B): least conserved, varies in length and amino acid sequence; activation function 1 (AF1); post-translational modifications
    • DBD (DNA Binding Domain, C): highly conserved, responsible for DNA recognition and binding; two zinc fingers formed by cysteine-rich loops
    • Hinge Region (D): o NLS1 overlaps with the end of DBD and the hinge region, o NLS2 overlaps with the LBD
    • Ligand Binding Domain (E/F): binds ligand

    The HPA Axis, Glucocorticoids, and Receptors

    • The HPA Axis: release of glucocorticoids (cortisol in humans); negative feedback mechanisms
    • Glucocorticoids: maintain homeostasis and respond to stress; regulate metabolic and immune responses; anti-inflammatory and immunosuppressive
    • Glucocorticoid Receptor (GR): encoded by the NR3C1 gene; alternative splicing of exon 9 → GRα and GRβ; GRγ contains an arginine insertion in the DBD

    The Glucocorticoid Receptor

    • N-terminal Domain (A/B): multiple post-translational modification sites
    • DNA Binding Domain (C): binds to specific hormone response elements (HREs)
    • Hinge Region (D): overlaps with the end of DBD and the hinge region
    • Ligand Binding Domain (E/F): binds ligand

    GR-mediated Signaling

    • Unliganded GR: resides in the cytoplasm, forms a complex with HSP90 and other chaperone proteins
    • Ligand Binding: GR dissociates from the complex, exposes nuclear localization signals, and is translocated into the nucleus

    GR-mediated Regulation of Gene Transcription

    • Direct Binding: GR dimer binds to GRE (GGAACAnnnTGTTCT) → ↑ gene transcription
    • Transrepression: GR binds to negative GRE (IR nGRE, CTCC(n)0-2GGAGA) → ↓ gene transcription
    • Tethering: GR binds directly to DNA-bound AP-1 or NF-κB
    • Composite: GRE-bound GR interacts with neighboring DNA-bound AP-1 or NF-κB

    Class II NR - RXR Heterodimers

    • Non-permissive RXR Heterodimer: e.g., thyroid hormone receptor or vitamin D receptor; heterodimer is activated by ligands of the partner NR, while RXR is silenced
    • Permissive RXR Heterodimer: e.g., peroxisome proliferator-activated receptor; heterodimer is activated by ligands of either NR, with synergistic effects when both NRs are activated

    Nuclear Receptors

    • Nuclear receptors are ligand-activated transcription factors with 7 subfamilies and 48 members.
    • They dimerize, bind DNA, and have an intracellular ligand-binding domain.
    • They act directly with DNA via recognition of response elements.

    Classification of Nuclear Receptors

    • Steroid nuclear receptors: ligand is glucocorticoid or estrogen, forms homodimers, and response element is INVERTED repeat.
    • RXR heterodimer: ligand is fatty acids, retinoic acids, or cholesterol, forms heterodimers, and response element is DIRECT repeat.
    • Dimeric orphan nuclear receptors: no known ligand, forms dimers.
    • Monomeric orphan nuclear receptors: no known ligand, acts as a monomer.

    Structure of a Nuclear Receptor

    • N-terminal domain (A/B): least conserved, varies in length and amino acid sequence, and has activation function 1 (AF1).
    • DNA binding domain (C): highly conserved, responsible for DNA recognition and binding, and has two zinc fingers formed by cysteine-rich loops.
    • Hinge region (D): links DBD and LBD, contains nuclear localization signal (NLS), and allows flexibility for conformational change after ligand binding.
    • Ligand binding domain (E/F): highly conserved, has a hydrophobic pocket formed by two α-helices, and has activation function 2 (AF2).

    Peroxisome Proliferator-Activated Receptors (PPARs)

    • PPARα: expressed in liver, heart, and brown adipose tissue, involved in fatty acid oxidation.
    • PPARβ/δ: ubiquitously expressed, involved in fatty acid oxidation.
    • PPARγ: expressed in white and brown adipose tissue, involved in adipogenesis, lipid metabolism, and insulin sensitivity.
    • PPARγ function: adipocyte differentiation, lipid metabolism, glucose homeostasis, and can be activated without ligand in extreme circumstances.

    Glucocorticoid Receptor (GR)

    • Maintains homeostasis, responds to stress, regulates metabolism and immune responses, and has anti-inflammatory and immunosuppressive effects.
    • GR has a negative feedback mechanism, and chronic use of glucocorticoids can lead to adrenal suppression.
    • GR is encoded by the NR3C1 gene, which undergoes alternative splicing to form GRα and GRβ.
    • GRα mediates the action of glucocorticoids, while GRβ contains an arginine insertion in the DBD.

    GR Signaling

    • Unliganded GR is a monomer that resides in the cytoplasm and forms a complex with HSP90 and other chaperone proteins.
    • Ligand binding leads to GR dissociation from the complex, exposure of nuclear localization signals, and translocation to the nucleus.
    • GR signaling involves kinases and non-genomic effects.

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    Explore the core concepts of pharmacology, including nuclear receptors, drug response, and patient outcomes. Learn about the structure and function of nuclear receptors and their response elements.

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