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Cell signalling

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					Cell signalling

 26 March 2007
                     Overview
• No cell lives in isolation

• In all multicellular organisms, survival depends on an
  elaborate intercellular communication network that
  coordinates the growth, differentiation, and metabolism
  of the multitude of cells in diverse tissues and organs.


• Errors in cellular information processing are responsible
  for diseases such as cancer, autoimmunity, and diabetes.
  By understanding cell signaling, diseases can be treated
  effectively and, theoretically, artificial tissues could be
  built.
• Cells within small groups often communicate by direct
  cell-cell contact. Specialized junctions in the plasma
  membranes of adjacent cells permit them to exchange
  small molecules and to coordinate metabolic responses;
  other junctions between adjacent cells determine the
  shape and rigidity of many tissues.
• In addition, the establishment of specific cell-cell
  interactions between different types of cells is a
  necessary step in the development of many tissues. In
  some cases a particular protein on one cell binds to a
  receptor protein on the surface of an adjacent target
  cell, triggering its differentiation.
• Eukaryotic microorganisms
  – Pheromones coordinate
     • Sexual mating
     • Differentiation
• Plants, animals
  – Extracellular signaling controls
     • Metabolic processes
     • Growth and differentiation
     • Protein synthesis
• Signal molecules produce responses in
  target cells that have receptors.
• In multicellular organisms
  –   Chemicals
  –   Small molecules (aa., lipid derivatives)
  –   Peptides
  –   proteins
• Some diffuse and bind to intracellular
  receptors
  – Steroids, retinoids, thyroxine
Cell signaling pathways
         Signal transduction

– Overall processes converting a signal into
  cellular responses
                 Cell Signaling

• Steps involved are:
  –   Synthesis
  –   Release from signaling cells
  –   Transport to target cells
  –   Binding to receptor and activation
  –   Signal transduction by activated receptor
  –   Specific changes
  –   Removal of signal (termination)
• Receptor activation
  – Secreted or membrane bound molecules
     • Hormones, growth factors, neurotransmitters,
       pheromones
  – Changes in the concentration of metabolites
     • Oxygen or nutrients
  – Physical stimuli
     • Light, touch, heat
  Three types of signaling in
           animals
– Endocrine
   • hormones
– Paracrine
   • Neurotransmitters
   • Growth factors
– Autocrine
   • Growth factors
     (cultured cells, tumor
     cells)
      Ligand binding and effector specificity

• Each receptor binds only a single ligand
  or a group of closely related molecules.
  However, many signaling molecules bind
  to multiple types of receptors

• Acetylcholine binds to different receptors
  on muscle cells (contraction), heart
  muscle cells (inhibition of contraction)
  and pancreas acinar cells (exocytosis of
  secretory granules), respectively
• Different receptors of the same class that
  bind different ligands generate the same
  cellular response
• In liver, ACTH, epinephrine and glucagon
  bind to different GPCRs; but all three
  activate the same signaling pathway
  (cAMP)
     Intracellular signal transduction

• Many receptors transmit signals via
  second messengers
• They rapidly alter the activity of enzymes
  or non-enzymatic proteins
  – Ca2+ triggers contraction in muscle cells
  – Exocytosis of secretory vesicles in endocrine
    cells
  – cAMP generates different metabolic changes
    in different type of cells
            Regulation of signaling

• External signal decreases
  – Degradation of second mesenger
• Desensitization to prolonged signaling
  – Receptor endocytosis
• Modulation of receptor activity
  – Phosphorylation
  – Binding to other proteins
Receptors
  Hormones Can Be Classified Based on
  Their Solubility and Receptor Location
• Most hormones fall into three broad
  categories:
• (1) small lipophilic molecules that diffuse
  across the plasma membrane and interact
  with intracellular receptors;
• (2) hydrophilic or (3) lipophilic molecules
  that bind to cell-surface receptors.
• Recently, nitric oxide, a gas, has been
  shown to be a key regulator controlling
  many cellular responses
     Classification of receptors
• Intracellular receptors (for lipid soluble
  messengers)
     • function in the nucleus as transcription factors to
       alter the rate of transcription of particular genes.
• Plasma membrane receptors (for lipid
  insoluble messengers)
     • Receptors function as ion channels
     • receptors function as enzymes or are closely
       associated with cytoplasmic enzymes
     • receptors that activate G proteins which in turn act
       upon effector proteins, either ion channels or
       enzymes, in the plasma membrane.
   Hormones bind to intracellular
receptors and to cell-surface receptors
Nitric oxide
       Intracellular Receptors
• Extracellular signal molecules are small,
  lipid-soluble hormones such as steroid
  hormones, retinoids, thyroid hormones,
  Vitamin D. (Made from cholesterol)
• These hormones diffuse through plasma and
  nuclear membranes and interact directly
  with the transcription factors they control.
Sequence similarities and three functional regions




– N-terminal region of variable length (100-500 aa); in some
  receptors portions of this region act as activation domain
– At the center, DNA binding domain, made of a repeat of C4-zinc
  finger motif
– Near the C-terminal end, an hormone binding domain, which may
  act as an activation or repression domain.
The intracellular receptor superfamily.
  Nuclear receptor response elements
• Some characteristic sites of DNA are called
  response elements and can bind several nuclear
  receptors.
• These repeat regions are arranged either as an
  invert repeat, or direct repeat.
  – Inverted repeat: glucocorticoid response element;
    estrogen response element
     • Repeats are separated by any three bases, implicating
       symmetrical binding of the receptor homodimer to DNA
• Receptors for vitaminD, retinoic acid and
  thyroid hormone bind to direct repeats as
  heterodimers,
• Second component of the heterdimer is
  RXR monomer (i.e, RXR-RAR; RXR-
  VDR)
• The specifity of the binding is determined
  by the spacing between repeats.
 Regulation of transcription activity

• Regulatory mechanisms differ for hetero-
  dimeric and homodimeric receptors
• Heterodimeric receptors are exclusively
  nuclear; without ligand, they repress
  transcription by binding to their cognate
  sites in DNA
  – They do so by histone deacetylation
• Homodimeric receptors are cytoplasmic in the
  absence of ligands.
• Hormone binding leads to nuclear translocation
  of receptors
• Absence of hormone causes the aggregation of
  receptor as a complex with inhibitor proteins,
  such as Hsp90
Early primary response (A) and delayed secondary response (B) that
result from the activation of an intracellular receptor protein.

				
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posted:11/9/2011
language:English
pages:30