Cell signalling

Cell signalling

1. Extracellular signal molecules

   • Hydrophobic molecules
     • Intracellular receptors
     • Pass across membrane
   • Hydropholic molecules
     • Cell-surface receptors
     • Ligand

2. Distance

   • Short
     • Contact dependent
     • Local mediators on neihbouring cells
       • Paracrine
       • Autocrine
   • Long
     • Synaptic
     • Endocrine

3. Gap Junctions

   • Narrow water-filled channels
   • Direct communication bypassing plasma membrane barrier
   • Two-way communication
     • Homogenise intracellular conditions
     • Spread effects of extracellular signals through small molecules
       • Ca2+
       • Cyclic AMP

4. Different cells can respond differently to the same signal

   • Due to different intracellular machinery
     • interprets
     • integrates
   • eg. acetylcholine
     • Decreases action potential in heart muscle
     • stimulates contraction in skeletal muscle
   • responds to specific combinations of signals

5. Types of receptors

   • Intracellular receptors
     • Nuclear receptors
       • ligand-modulated gene regulatory proteins
       • Steroid hormones
         • Retinoids
         • Vitamin D
       • alter ability of receptor to control transcription of gene
       • Activates or inhibits bind DNA & transcription
     • Bind small hydrophobic molecules
   • Cell surface receptors
     • Ion-channel-coupled receptors
       • aka transmitter-gated
       • ionotropic receptors
       • Rapid signalling
       • mediated by transmitters
         • open or close channel
       • multipass transmembrane protein
     • G-protein-coupled receptors
       • GPCR
       • Senses outside cell, activate intracellular pathways
       • Indirectly regulates another membrane-bound target protein
         • Enzyme
         • Ion channel
       • G-protein mediates interaction between an activated receptor and the target protein
         • trimeric GTP-binding protein
           • Relays signals from GPCR
       • Multipass transmembrane proteins
         • 7 TM domains
       • Largest family of cell-surface receptors
       • Same signal molecule can activate many GPCRs
       • Half of all known drugs work through them or the pathways they activate
       • Some regulate the production of cAMP
     • Enzyme-coupled receptors
       • function directly asn enzyme
       • associate with enzymes that they acticate
       • single-pass TM proteins
         • Ligand binding site on outside
         • Activating site inside
       • Protein kinases or associate with protein kinases
       • 6 principal classes
         • Receptor tyrosine kinases
           • Phosphorylates tyrosines on themselves and on some intracellular signalling proteins
           • TTKs
           • ~60 genes encode human RTKs
           • Ligand binding causes RTK to dimerise, bring two kinase domains close together
             • Cross phosphorylate each other on multiple tyrosines
               • GTPase Ras mediates signalling
                 • Ras superfamily consists of monomeric GTPases
     • Act as signal transducers

6. Second Messengers

   • intracellular signalling molecules
   • Initiators of intracellular signal transduction cascades
   • Bind to & alter intracellular signalling proteins or effector proteins
     • Intracellular signalling proteins
       • Molecular switrches
       • From inactive to active onformation when receiving a signal
       • Two classes
         • Depend on gain or loss phosphate
         • signaling by phosphorylation
           • protein kinase
             • Protein phosphatase
         • Signaling by GTP binding
           • GTP binding
             • GTP hydrolysis

7. Response time

   • Quickest synaptic
   • Quick movement, secretion, metabolism
   • Slow change ene expression

8. Feed back

   • Positive
     • Output stimulates its own production
     • Steep or all-or-non response
     • Can persist after signal drops
   • Negative
     • Output inhibits its own production
     • Limit level of response
     • Short delay, brief abrupt response
     • Long delay, oscillations