Midterm #3: Signal Transduction Flashcards Preview

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Flashcards in Midterm #3: Signal Transduction Deck (19):

Intercellular vs. Intracellular Signal Transduction, Incoming Signals, Initial Receptors

  • Intercellular Signal Transduction: a signal passes from one cell to another
  • Intracellular Signal Transduction: the receiving cell biochemically decodes that signal
  • Signals may include: gas (NO), amino acid (glutamate), steroid (estrogen), peptide hormone (insulin), protein (growth factors)
  • The initial receptors: may exist on the surface of the cell (cell surface receptors) or within it (intracellular/nuclear receptors)


Intracellular Communication Mechanisms: endocrine, paracrine, autocrine, juxtacrine, matricine

  • Endocrine: specialized sender cells (glands) synthesized and secrete molecules (hormones) into the blood. All cells are exposed, but only those containing the appropriate receptors are affected
  • Paracrine: Sender cells secretes molecules into the local environment only (local mediators)
  • Autocrine: Sender cell secretes molecules into the local environment and receives them itself
  • Juxtacrine: Cell-to-cell contact
  • Matricine: cell to extracellular matrix


Nuclear Receptors

  • Hydrophobic Small Molecules
  • Diffuse through plasma membrane and bind to intracellular receptors
    • Transcription Factors


Type 1 Nuclear Receptor

  • bind to ligand in the cytoplasm
  • homodimerize
  • translocated into the nucleus (via nuclear pore complex)
  • bind to transcription element
  • initiate transcription
  • Examples:
    • sex hormone receptors
    • glucocorticoid receptor
    • mineralcorticoid receptor 


Type II Nuclear Receptor

  • constituitively exist in the nucleus in DNA bound heterodimers
  • Often bound to a corepressor protein 
  • Ligand binding triggers dissociation of the corepressor and association of a coactivator 
    • allows the recruitment of RNAP and initiation of transcription 
  • Examples:
    • thyroid hormone receptor (TR)
    • retinoic acid receptor (RAR)
    • aryl hydrocarbon receptor (AhR)*
    • pregnane X receptor (PXR)*
    • constituitive androstane receptor (CAR)*
    • *binds to xenotic response elements, important for CYP induction  


Cell Surface Receptors

  • binds to ligands at the extracellular surface
  • wide variety of ligands, small molecules, peptides and large proteins
  • Receptor Tyrosine Kinase, G-Couple Protein Receptors


Receptor Tyrosine Kinase (RTK) Family

  • Bind growth factors and certain hormones
    • cytokines
  • Trigger intracellular phosphorylation cascades to cause effects


G-Coupled Protein Receptors

  • bind a wide variety of ligands
  • intracellular second messanger to ellict their effects


Receptor Tyrosine Kinase Mechanism

  • Hormone binding extracellular domain activates cytosolic tyrosine kinase domain
    • autophosphorylates specific Tyr residues and activates the receptor 
  • Activated receptor binds to and phosphorylates Tyr residues on specific target proteins, which are often kinase enzymes themselves 
  • Examples:
    • insulin receptor
    • EGFR (epidermal growth factor receptor)
    • VEGFR (vascular endothelial growth factor receptor)


EGFR as Therapeutic Target

  • EGF binding to EGFR stimulates cell proliferation 
  • EGFR-targeting drugs include 
    • monoclonal antibodies such as cetuximab (Erbitux)
      • inhibit EGF binding
    • small molecules like erlotinib (Tarceva)
      • inhibit autophosphorylation and downstream signaling 


VEFGR as Therapeutic Target

  • VEGF binds VEGFR and stimulates blood vessel growth  (angiogenesis/vasculogenesis)
  • Important in tumor growth and age-related macular degeneration
  • Bevacizumab (Avastin) is approved for certain cancers and used off label to treat AMD
  • Ranibizumab (Lucentis) is a fragment of the same mAb approved to specifically treat AMD 


What is this structure?

Erlotinib (Tarceva)


G-Protein Coupled Receptors (aka 7TM Receptors) Mechanism


  • 7 TM alpha helices bundled together
  • Cause downstream effects through GTP-ases called G-proteins
  • Resting state:
    • GPCR associate with heterotrimeric G-proteins (alpha, beta, and gamma) with the Ga bound to GDP
  • When ligands bind:
    • Undergoes confirmational changes that causes Ga to release GDP and bind GTP
    • Ga dissociates from Gbg with activates both complexes
    • Complexes interact with downstream effectors (like adenylate cyclase and phospholipase C) to change second messanger levels 
  • Activation of G protein is short lived
    • Ga slowly hydrolyzes GTP and Ga-GDP rebinds Gbg to reassemble the inactive heterotrimer


cAMP second messanger signaling by GPCR

  • Adenylate cyclase is a membrane bound protein that catalyzes the synthesis of cAMP
  • Activated Ga subunits regulate the activity of adenylate cyclase: Gas stimulates and Gai inhibits
  • cAMP regulates the activity of protein kinase A 
  • PKA is an inactive heterotetramer consisting of 2 regulatory and 2 catalytic subunits 
  • cAMP binds the regulatory subunits which release the active catalytic subunits 
  • Activated PKA subunits then phosphorylate Ser and Thr residues on target proteins 


cAMP Second Messanger Signaling in Muscle Cell

  • epinephrine binds to alpha-adrenergic receptor and activates associated Gas
  • This activates adenylate cyclase, which generates cAMP, which activates PKA
  • PKA phosphorylates:
    • glycogen synthase (inactivation)
    • phosphorylase kinase (activation)
  • Glycogen is broken down to glucose to power muscle
  • PKA also phosphorylates ser and thr residues on the insulin receptor and decreases it's catalytic activity 


The Phosphoinositide Cascade 

  • Mediated by phospholipase C
  • Binding of hormone (ex: serotonin) to membrane receptor activates trimeric G-protein that then activates PLC (an integral membrane protein)
  • PLC hydrolyzes phosphatidylinositol (PIP2) to diacyl glycerol (DAG) and inositol triphosphate (IP3)
  • IP3 diffuses into the cytosol and binds to ligand-gated calcium channels in ER
  • calcium is yet another second messanger. 
    • DAG and calcium activate protein kinase C, which is a ser/thr protein kinase involved in cell growth and differentiation 


Therapeutic Approaches to GPCR Signaling 

  • Antihistamines like loratadine (blocks the histamine H1 receptor)
  • Heartburn meds like rantidine (histamine H2 receptor antagonist)
  • Antipsychotics like perphenazine (blocks dopamine D2 receptor)
  • Second messangers can also be targeted:
    • phosphodiesterases degrade cAMP and return adenylate cyclase cascade to resting state
    • Methylxanthines like caffeine and theobromine inhibit phosphodiesterases and prolong the effects of cAMP, potentiating the adenylate cyclase system 


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