Cell Surface Receptors by linzhengnd


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                                           Cell Surface Receptors
                                           Structure and Function
               1. There are Classifications of Cell Surface Receptors – They are classified on the
                   basis of what they bind to, what are their ligands or cargo.
                        a. Ligands (“cargo”): There are different types of receptors with in classes
                           of receptors  these are receptor subgroups.
                                i. Hormones, neurotransmitters, growth factors
                                      1. Hormones bind to receptors that stimulate secretion:
                                          neurotransmitters are highly expressed in the brain and
                                      2. Growth factors stimulated the cells to divide (ex. Insulin,
                                          platelet derived growth factor.
                               ii. Nutrients, vitamins
                                      1. B-12
                              iii. Immunoglobulin
                                      1. Antibodies are most highly expressed on cells of the
                                          immune system.
                              iv. Adhesion
                                      1. Cells have to stick to connective tissue or other epithelial
                                          cells: Cell substratum adhesion
                                      2. Some cells like to stick together  these regulate cell
                                          adhesion and/or motility.
                                               a. Important consequences in diseases like cancer, the
                                                  cells move around cells of the immune system
                                                       i. They have to escape thru the blood vessels,
                                                          in surrounding tissue.
                                                      ii. Clear alter cell-cell connection and their
                                                          barrier to move thru.
                               v. Ion channels
                                      1. These are most commonly seen in the nervous system.
                                               a. Ach receptor at the neuromuscular junction, binds
                                                  to the Ach receptor on muscle cells and channel
                              vi. Infections agents
                                      1. Theses bind to the cell surface receptors and have evolved
                                          to bind to proteins expressed on a particular cell.
                                      2. They can also bind to cell surface lipids  characteristic
                                          of what types of receptors specific cells like to bind to:
                                               a. CD4 (HIV likes to bind to this)  if we can prevent
                                                  to binding cells will be protected against HIV.
                        b. Signaling Receptors  Signal Transduction (immediate and long-
  There is immediate       term) upon ligand binding. These just refer to the process these
(secretion, movement,      receptors mediate signal transduction  the different categories.
 and endocytosis) or    c. Signal transdution is how the cell interprets the signals.
    long term effect d. Signalling receptors are typical targets of drug molecules.
(proliferation of cells         i. G-Protein Coupled receptors
 or some phenotypic                   1. These have a well defined membrane topology  all are
   change))  DNA                         coupled to GTPases.
 synthesis function of
the cell: turn genes on
        and off.                                                                                   1
                      Okamoto                                            2
               Cell Surface Receptors
               Structure and Function
                a. Ligand binds and the G-protein is activated  this
                    activates other proteins, and starts a cascade effect
                    that gets amplification.
                b. There is generation of a 2nd messenger  cAMP,
                    Ca2+ , or alteration of lipid metabolism that leads to
                    the generation of DAG and IP3.
        2. Ex: 7 transmembrane domain (TMD) receptors
        3. Coupled to heterotrimic GTPases which regulated enzymes
            (coupled to GTP binding proteins)
                a. The GTPases are on the Cytoplasmic domain and
                    the receptors are on the extracellular side.
                b. Their phosphorulation begins as intracellular
                    signaling cascade.
                c. The activation of IP3 and DAG is a result of
                    phospholipase C (PLC) which works on the lipids
                    (lipid metabolism) in the membrane and hydrolyzes
                    it, this activates protein kinases.
                          i. Then IP3 and DAG stimulate other process,
                              such as causing increases in calcium.
                d. Ex. Adenylate cyclase may be activated, this
                    increases cyclic AMP, and then activates protein
                    kinases…get a cascade so a single signal may
                    multiply  some 2nd messenger is activated.
ii. Intrinsic tyrosine kinase (enzymatic) activity – These receptors
    have a single transmembrane domain  will phosphorulate
    tyrosine residues of the target proteins (mechanism be which you
    can turn the protein on or off).
        1. Kinase has enzymatic activity that leads to the
            phosphorulation of proteins  the protein often acts as a
            molecular switch.
                a. There are tyrosine, serine/threonine kinases.
        2. Epidermal Growth Factor, nerve growth factor, platelet-
            derived growth factor, insulin.
                a. When a ligand binds, the tyrosine kinases are
                    stimulated and the phosphorulate their partner.
                b. The tyrosine residues dimerize in the plasma
                    membrane, this begins the signaling process 
                    dimerization upon ligand binding
                          i. Once the ligands bind a cascade of events
                              is stimulated and other cell proteins
                              recognize the complex (serves as a binding
                              site for other cell proteins).
                         ii. Now other Cytosolic proteins can be
                              phosphorulated, which activates or
                              deactivates other Cytosolic proteins

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                                 Cell Surface Receptors
                                 Structure and Function
                                        iii. The phosphorulation serves as a signal to
                                             initiate a series of events, which leads to the
                                             activation or deactivation of cell activities.
                                                  1. Think of the phosphorulation as a
                                                      molecular switch.
                                        iv. The effects can be short term or long term
                                             (such as cell proliferation)

                   iii. Linked to non-receptor tyrosine kinases
                           1. Tend to be single transmembrane domain receptors that
                              bind to ligands.
                           2. They DO NOT HAVE intrinsic tyrosine kinase activity.
                                   a. When the ligand binds, non receptor tyrosine kinase
                                      causes the phosphorulation.
                                           i. Once the ligand binds, there may be a
                                              conformation change.
                                          ii. May already be associated with the receptor
                                              and the ligand may initialize the
                                              conformation that activates.
                                         iii. When a ligand binds, a non receptor tyrosine
                                              kinase can associate with the receptor and
                                              then phosphorulate the proteins on their
                                         iv. Then the complex behaves as a scaffolding
*The proteins that are phosphorulated are tyrosines that are associated with specific
amino acids (a motif)  not every tyrosine is phosphorulated, only the ones with the
special motif are recognized and phosphorulated, and only the target proteins have the
special motif.
                           3. growth factors

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                               Cell Surface Receptors
                               Structure and Function
                        4. immune function

                        Two Types of Tyrosine Kinase
    Intrinsic Type Tyrosine Kinase           Linked to non-receptor tyrosine kinases

         1 – 2 proteins usually
     Span the membrane one time                   Span the membrane one time
The extracellular domain forms a ligand      The extracellular domain forms a ligand
            binding domain                               binding domain
 The intracellular domain is a tyrosine        When a ligand binds, a non receptor
                 kinase                       tyrosine kinase can associate with the
                                              receptor and then phosphorulate the
                                                    proteins on their tyrosine.
Can dimerize and then they phosphorulate             NO DIMERIZATION
         their binding partner.
When the ligand binds to the receptor,
        activity is stimulated.

         e. BOTH Tyrosine kinase receptors are a focas of many pahramacuetis R and
            D because they are most clearly linked to cancer issues.
                i. Ex. Cell proliferation  try to block the signal transduction
               ii. Ligand-gated ion channels
                       1. These change the membrane potential because they are
                          ligand gated ion channels.
                               a. Ach R  on the muscle cell at the neuromuscular
                                   synapse; mostly lets monovalent ions in.
                               b. GABA R  lets Chloride ions in
                               c. Glu R  glutamate receptor; lets chloride ions in.
                       2. Each different one opens different channel types and
                          potentially let different ions in.
                       3. An inhibitory signal makes the membrane potential more
              iii. TRP Channels  transient receptor potentials.
                       1. New class of channels.
                       2. First identified in fruit flies (photoreceptor cells)
                       3. Many participate in mediating sensory effect, have taste
                          ones, or cold or heat or chemicals that stimulate the cold or
                          heat (such as menthol).
                       4. These behave as channels, typically cation selective
                       5. They are very important in sensory aspect of organisms.
         f. Macromolecular Ligands
                i. Nutrients –
                       1. LDL, HDL

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                            Cell Surface Receptors
                            Structure and Function
                     2. Transferrin
                     3. Vitamin B12 intrinsic Factor
              ii. Immunoglobulins
                     1. dIgA transcytosis
                     2. IgG transcytosis
             iii. Cell-cell, cell-substratum attachment
                     1. Tight Junction Protiens: cell-cell
                     2. Cadherins: cell-substrate
             iv. Infectious Agents
                     1. Bacteria, parasites, viruses
                     2. Toxins derived therefrom
2. Characterization of Cell-Surface Receptors:
     a. Detection by Binding Assays
             i. Specificity  ionic, van der Waals, hydrogen bonds, hydrophobic
                interactions between the ligand and receptor
            ii. Affinity (micromolar to less than nanomolar range)
                    1. Relative to Biological Response
                    2. Relative to levels of circulating hormones
           iii. Scatchard Plots
                    1. K: binding constant per site
                    2. N: number of binding sites pre mole of receptor
     b. Internalization (receptor-mediated endocytosis)
             i. Functions of receptor-mediated endocytosis
                    1. Sequester receptor away from the plasma membvrane
                    2. Process ligand
                            a. Degradation to terminate signaling
                            b. Degradation to use component parts
                            c. Post-endocytotic trafficking to toher compartments
                            d. Sampling of environment
            ii. Assays for Endocytosis:

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    Cell Surface Receptors
    Structure and Function



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