Session 2 Receptors and their classification

• Steps in cell signaling?

  • Reception
  • Transduction
  • Cellular response
• Juxtacrine- cells in direct cell to cell contact communicate via cell surface signalling molecules.
• Efficacy = describes the maximum biological response that a drug can produce, irrespective of concentration.
• Potency = describes the effectiveness of an agonist to produce a biological response (effective concentration of an agonist required to produce 50% of the maximum response (EC50).
• Receptors with no identifiable ligand = Orphan Receptor
• Typical structure of ionotropic receptors - Pentamer; ligand binding sites on each alpha subunit, 4 transmembrane domains.
• Example of typical ionotropic receptor - nicotinic receptor
• Non-typical Structure of Ionotropic Receptors - tetramer
• Example of non-typical ionotropic receptor - ionotropic glutamate receptor
• AMPA receptors permit influx of sodium ions to depolarise the postsynaptic membrane.
• NMDA receptors permit calcium influx following depolarisation; they are blocked by magnesium ions.
• Pharmacological targets for treatment of neurological and psychiatric conditions. Also used for anaesthesia, chronic pain - ligand gated ion channels
• Pharmacological targets for treatment of cancers, metabolic diseases (obesity, diabetes), neurological, cardiovascular, autoimmune conditions - enzyme linked receptors
• Example of tyrosine linked receptors?

  Insulin receptor
• Structure of tyrosine/kinase linked receptor

  • 2 alpha subunits and 2 beta subunits
  • αsubunits are linked with each other and with β subunits by disulphide bridges
  • The extracellular domain of α subunits have binding sites for insulin
  • Transmembrane domain
  • The intracellular domain of β subunits have intrinsic tyrosine kinase activity.
• Example of nuclear intracellular receptor?

  thyroid receptor
• Example of cytoplasmic intracellular receptor?

  steroid receptor
• Structure of Intracellular Receptor

  • Monomeric with ligand binding domain within the C terminal region, DNA- binding domain in the central region of the receptor and N-terminal region is responsible for transcriptional regulation
  • The hinge region connects ligand binding domain with the DNA binding domain.
• Steroid hormone pathway:

  The inactive receptor forms a complex with HSP90 (heat shock protein)

  It blocks a region called the hinge site

  When hormone binds, HSP90 dissociates, and the hormone-receptor complex enters the nucleus.

  Entry is facilitated by a nuclear localisation signal (NLS) that is located at the hinge site.

  dimerization occurs, and the hormone-receptor complex interacts with DNA to influence gene expression.
• Pharmacological targets for treatment of cancers, diabetes, hyperlipidaemia, inflammatory and dermatological conditions - intracellular receptors.
• G - proteins -> guanine nucleotide-binding proteins
• Pharmacological targets for treatment of hypertension, gastrointestinal, neurological, inflammatory and mental health disorders, chronic pain - GPCRs
• Structure of GPCRs

  • Monomers consisting of 7 transmembrane domains
  • Extracellular N-terminal region or 2-3 transmembrane domains are ligand binding sites
  • Intracellular C-terminal region interacts with G proteins.
  • G proteins consist of α, β and γ subunits
• Endocytosis is the process by which substances enter a cell through the process of engulfment.
• Three types of endocytosis

  1. Phagocytosis
  2. Pinocytosis
  3. Receptor mediated endocytosis
• Phagocytes also have lysosomes which are membrane-bound organelles containing hydrolytic enzymes. These fuse with phagosomes and release their cargo into the phagosome, degrading any internalised particles.
• Phagocytes recognize PAMPs in pathogens via PRRs
• Examples of phagocytes?

  • Neutrophils
  • Dendritic cells
  • Macrophages
• Clinical relevance of phagocytosis?

  • Neutropenia- low neutrophil count, high risk of infections, particularly bacterial and progression to septic shock
  • Chronic granulomatous disease- NADPH oxidase deficiency, cannot kill pathogens via phagocytosis, leads to chronic inflammation and granuloma formation and persistent infections
  • Management via antibiotics
• Takes up particles into the cell by invagination of the cell membrane - receptor mediated endocytosis
• Function of endosome?

  To transport extracellular material into the cell.
• Viruses and receptor-mediated endocytosis?

  • haemagglutinin (HA) of influenza virus binds with sialic acid on the surface of cell membranes in the upper respiratory tract
  • Gp120 of HIV-1 binds to CD4 receptors on Th cells.
• HIV and receptor mediated endocytosis?

  • CCR5 is a protein on the surface of CD4+ cells - HIV-1 binds via the CCR5 co-receptor on CD4+ Th cells to enter and infect host cells.
  • A few individuals carry a mutation in the CCR5 gene meaning that some HIV-1 strains can no longer enter the cell via the CCR5 receptor. - CCR5 co-receptor antagonists prevent HIV-1 from entering the cell by blocking the CCR5 cell surface co-receptor.
• The placenta ensures foetal growth and health by ?

  • Mediating nutrient uptake from maternal blood
  • Waste removal from foetal blood
  • Providing a protective barrier to toxins and pathogens
• the histological barrier of the placenta, which consists of two cell layers: syncytiotrophoblasts and endothelial cells of the foetal capillaries.
• Transferrin (iron) and Cobalamin (B12) transfer across the placenta via receptor mediated endocytosis.
• The placental transfer of maternal immunoglobulins to the foetus is a specific adaptative mechanism that confers short term passive immunity
• Functions of Type G immunoglobulins?

  • neutralise toxins by directly binding to them
  • bind to antigens on pathogen surfaces. This agglutinates them to impair their mobility and also opsonises them to enhance phagocytosis.
  • The binding of antibodies to antigens to form complexes activates the classical complement pathway (activates complement system)
  • They also directly activate effector cells such as dendritic cells, NK cells and cytotoxic T cell
• IgG bind to FcRn receptors in endosomes of the placental syncytiotrophoblasts. Following the pH gradient between the acidic endosome and foetal blood, maternal IgG then travels into the foetal circulation.
• Zika virus is a single-stranded RNA virus of the Flaviviridae family (genus Flavivirus)

  Transmission to humans is primarily through the bite of an infected Aedes species mosquito.