How do cells Communicate
     a - 
in multi-cell organisms contact between cells is critical for inter-cell communication*.
     b -  cell membranes contain specific protein RECEPTORS, which bind &/or transmit
extra-cellular SIGNAL MOLECULES converting signals into specific cellular response

Some UNIVERSAL PRINCIPLES of cell communication are now well understood:
cells use many different signal molecules and receptors, for many cell functions. 

            - and a simple mechanism of signal/reception has survived throughout evolution.

                  - an analogy: auto industry... cars basically have same parts (engines, fenders, lights)
                    and the variety of different shapes and patterns may be boundless.

A key mechanism of Cell to Cell Signaling is SIGNAL TRANSDUCTION*...
           Here an exogenous signal molecule is received by a cell receptor and,
                          converted (transduced) into a response by the receiving cell.

      This pattern is remarkably similar in all cells;  probably evolved very early, 
                          even before multicellularity (maybe even in single cell prokaryotes),
                          and has been highly conserved in today's progeny of ancestral cells.








  Cell Signaling can be LOCAL or DISTANT...

         local regulator chemical messengers are targeted to specific receptors 
         often includes: growth factor proteins that promote cell division & growth
                  & neurotransmitters that move across synapses to other neurons

  ENDOCRINE (distant) SIGNALING:                                              examples*    
          specialized cells release molecules (often hormones) into blood vessels of
          circulatory system,  hormones move to distant target cells... elicit response


  Cell to Cell SIGNALING SYSTEMS...  a few examples... 

   haploid cell mating in yeast cells*         (picture of asexual budding in yeast cells)
       sex-1    ["a"-cell : releases a-factor (peptide of 12 aa's) - binds to sex-2 receptors]
       sex-2    ["
α"-cell : releases α-factor - binds to sex-1 receptors]
                                   the result is fusion of 2 cells (a mating) producing diploid cell.











                    - is where signaling is due to direct contact exchanges...
                    - probably how cell c
ommunication may have begun?

                  gap junctions & plasmodesma...
                          results in cytoplasmic continuity favoring cellular interactions...

                                          fig 11.4a*

                  cell surface contacts... 
                          receptor protein specificity
(as above with yeast cells
                          cell to cell contact is likely how multicellularity began?

fig 11.4b*

  Cell Signaling often works via MOLECULAR SWITCHES...   examples*  








             the universal model of a Signal Transduction Process has 3 stages...

                           RECEPTION,   TRANSDUCTION,  and  RESPONSE      

    1st.   RECEPTION...  is not unlike recognition of enzyme for its substrate [ES complex]
              ... akin to the lock-&-key hypothesis of enzyme-substrate recognition (Km & Vmax
              ... ligand (signal) molecules (usually water soluble) are recognized by
                                  only one receptor protein bound within a cell membrane.


    2nd.  TRANSDUCTION...  
a conformation change in a receptor leads to
              ... shape and activity changes in other intra-cellular molecules
              ... which may result in multiple, conformational changes in other cellular proteins

                    a cascade
* of inactive enzymes ---> active enzymes, & so on, etc...

    3rd.   RESPONSE...  usually a cellular activity, as enzyme activation or catalysis, or
                               rearrangement of cytoskeleton (movement), or specific gene activity.

Signals & Receptors*  &  specific example  Fig 11.6 - Sutherland & cAMP*    
     Pp2 - Pp5













a Generic Example of a Receptor Protein & Signal Transduction System:

G-Proteins  &  G-Protein Coupled Receptors... 
            membrane receptor proteins that bind
& switch between
            active & inactive forms. Some 50 to 100 GTP binding G-protein are estimated.
(R. Lefkowitz & B. Kobilka - 2012 Nobel Prize-GPCRs)

      G-protein receptor structure... has 7 transmembrane
                & has site for signal molecule and G-protein to bind
                      fig 11.8a


      a signal molecule binds to a receptor -&-> conformational change occur --> 
               G-protein structure
* is inactive when GDP is bound to alpha subunit.
               an inactive G-
(GDP)-protein now binds GTP (replacing GDP)...            
               and active G-
-protein stimulates other inactive enzymes...        fig 11.8b*
                    adenylyl  cyclase  structure
       if G-Protein has its GTP hydrolyzed   -->   it inactivates G-protein...      
                      (Cholera & Botulin toxins... keep G-proteins active -->

an Example of Scale via G-protein responses involving a 2nd messenger molecule:
       "Fight or Flight Response"...
  (see fig 11.12
*)  is due to a phosphorylation cascade 
magnification... 1 signal molecule gives multiple-enhanced response - fig 11.16*
                                    Summary animation of glycogen breakdown*review

   another examples:    another 2nd messenger = IP3 & Ca ions*   







         While the basics of Signal Transduction are simple in design
         the specificity of cell signaling is varied among cells
and can lead to a...

         a Multiplicity of Signal Transduction Responce Mechnaisms*  

           cAMP signaling is extensive in cellular function*

     Specific Case Examples: 

         1. Aldosterone reception & kidney regulation    -  Campbell 11e- figure 11.15*

        2. Ligand gated ion channel signaling               -  Campbell 11e- figure 11.8*

         3. Cortisol and nuclear receptors                         -  Campbell 11e- figure 11.15*

        4.  Signal Transduction of gene activation          - 
Signals & Gene Action*review     

                                    a Summary review of Receptors in Cells*review

             copyright c2024     Last update -  March 2024
  Charles Mallery,    Department of Biology,   U.of Miami,  Coral Gables, FL 33124          

           bckac.       next lecture.      











 you are not responsible for the material that follows below:

 - Janus tyrosine kinase & inflammation* 


other examples of Receptor Proteins & Signal Transduction Systems...

2. Tyrosine Kinase receptors...  receptor proteins that have kinase activity...
            i.e., they can add a
-PO4 group to tyrosine residues of inactive proteins 
                  making them active   --->   cell response                              
fig 11.8*
         many growth factors (stimulate cell division & growth) function via

      ...  binding of growth factor (signal ligand) causes 2 single tyr-kinases to aggregate
     ...  the tyr-dimers, now each phosphorylate the others tyr residues via ATP kinase activity
     ...  the activated-phosphorylated dimer binds relay proteins, activating them,
                    which in turn (by cascade effect) can active up to 10 others, etc...

               net result... 1 signal molecule can trigger many proteins and multiple pathways.










more examples of Receptor Proteins & Signal Transduction Systems...

  3.  Ion channel Receptors...  [ligand gated protein channels]
              a protein
PORE in a membrane opens in response to binding a signal molecule
ex: a neurotransmitter as acetylcholine (Ach) opens channel and lets Na+ ions 
                     flood into cell, changing that cell's electrical charge (potential)
see fig 11.9*

                              How Potassium ion Channel works - 2003 Nobel Prize in Chemistry   H2O
   4.  Non-membrane bound [cytoplasmic - intracellular] Receptors...
             signal molecules diffuse through membrane, where binding to an 
intracellular receptor protein initiates a cellular response.
                                               ex:  steroid hormones  (
see fig 11.10*)

          back to outlines                                                      key concepts*

                 copyright c2010     Last update -
next      Charles Mallery,    Biology 150, Department of Biology,   University of Miami,  Coral Gables, FL 33124
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  the material below is not required reading.


  Review of Some Important Points of SIGNAL TRANSDUCTION PATHWAYS

        most are like dominos... one activates another, then another, then another...
                                    producing a significant cascade multiplication effect.

1.    an Enzyme Cascade* - a model phosphorylation cascade effect...
              enzyme activation is by protein phosphorylation by protein kinase enzymes,
              that transfer P from ATP to another enzyme protein, thereby activating it.

2.     2nd messenger signal molecules...        cyclic-AMP           [cAMP = see fig 11.11*]
              signal molecule (hormone epinepherine) leads to activation
                    of membrane bound inactive enzyme Adenyl Cyclase
                                 ATP   ---
active adenyl cyclase--->   cyclic-AMP  
                    ( cAMP is inactivated by phosphodiesterase ).

              G-protein &  cAMP activation of protein-kinase-A                  see fig 11.12*
                             PKA, itself a kinase, can activate other proteins, etc...
                                (see epinepherine & glycogen breakdown -   
see fig 11.15*








some more POINTS of cell communication via signal transduction:

3.  cholera  toxin 
Vibrio cholerae grow in fecal infected waters, infect small intestine,
        produce toxin, which binds to a G-protein, prevents conversion of GTP --> GDP,
        thus G-protein remains active, causing cAMP to remain active....
                net result: small intestine secretes water and salts = perfuse diarrhea = fatal.

4.  Ca ions
       cells maintain a low cytoplasmic [Ca] by active transport of Ca out of cytoplasm
       pumps keep a low cytoplasmic [Ca], but high ER cisternae & mitoplasm [Ca]
  see fig 11.14*

               Ca itself functions as a 2nd messenger, like cAMP,
                       as [Ca] in cytoplasm goes up, activates Ca+ pumps, & other responses ensue...
                                 as muscle contractions, neurotransmitter release, etc...

5.   plant phytochrome action via G protein & Ca channels = greening*
        plant pigment involved in responses to light - seed germination, photoperiodism, flowering, etc... 








6.  gene activation via cascading signal transduction.            see fig 11.17*















5.   Other 2nd messengers and Ca activation...
                Diacylglycerol (DAG)   and   Inositol Triphosphate (
IP 3)

        a.  signal molecule binds to a G-protein or a tyrosine-kinase receptor
        b.  G-protein  activates  phospholipase-C,   an enzyme that splits lipids
        c.  phospholipase-C splits the phospholipid,
PIP 2, into   DAG  &  IP 3
IP 3, as a ligand, binds to Ca ion channel of ER and increases cytosol [Ca]
       e.  increased Ca binds to enzyme calmodulin, changes its conformation, which
        f.  activates additional kinases and/or phosphatases. 
   see figure *



















           Some specific examples of G-protein cellular responses:
                mouse embryos lacking one G-protein... show no blood vessel development
                some human embryos w/o  G-proteins... decreased senses (esp: vision & smell)
                cholera and botulin toxins... function by interfering w G-proteins.






    &     Logic Circuits   
Gene Action signaling*
Medical applications include Drug Action, & Drug Allosterism 
           animation of 2nd messenger*      

           Video of binding of hormone to its receptor followed by effects it triggers*view@home