Cell structure

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  1. About 200,000 distinct mRNA sequences are expressed in neurons of the brain (10-20 times more than any other organ)
  2. mRNA gives rise to three types of proteins
    1. proteins that are synthesized in the cytosol and remain there (translated on free ribosomes)
      1. cytosolic proteins comprise two separate groups:
        1. fibrillary elements that make up the cytoskeleton (neurofilaments, tubulins, and actins)
        2. enzymes that catalyze reactions (e.g. choline acetyltransferase)
      2. mRNA molecules for cytosolic proteins emerge through nuclear pores and become associated with ribosomes to form free polysomes in the neuron’s cytoplasm; one end has a free amino end (N-terminal) and the other a carboxyl (C-terminal). Translation begins at the N terminal end
        1. most important cotranslational modification is N-acetylation, the transfer of an acyl group to the N-terminus
        2. the acyl group is activated by coupling to CoA, the universal metabolic intermediate for transferring acyl groups
        3. another important modification is phosphorylation (dinitrophenol, a chemotherapeutic agent, interferes with this)
    2. proteins that are synthesized in the cytosol and translated on free ribosomes but are later incorporated into the nucleus, mitochondria or peroxisomes (mitochondria and peroxisomes are involved with oxygen metabolization)
      1. reach their destination after synthesis has been completed on free ribosomes whereas most membrane and secretory proteins reach their destination by cotranslational transfer (see below)
    3. proteins synthesized in association with the cell membrane system (form polysomes that become attached to the flattened sheet of the ER) including:
      1. those attached to the endoplasmic reticulum (ER) and Golgi apparatus
        1. membrane spanning
        2. membrane anchored
        3. membrane associated
      2. those that remain within the lumen of the ER or Golgi sacs but not attached to the membrane
      3. those that are distributed by vesicles that bud off from the trans face of the Golgi apparatus
      4. mRNA encoding proteins destined to become secretory products or constituents of organelles are formed on polysomes that attach to the endoplasmic reticulum (rough endoplasmic reticulum)
        1. peptide is transported through the lipid bilayer into the lumen of the endoplasmic reticulum where the signal peptide is cleaved by signal peptidase; the polypeptide continues to grow in length at its C-terminal end
        2. the most common configuration is partial transfer through the membrane resulting in an integral membrane protein with its C-termminus on the cytoplasmic side (Remember ‘c’ and ‘c’ytoplasmic) and its N terminus on the luminal side of the endoplasmic reticulum; however, if the sequence is not cleaved and translocation continues, the result is an integral membrane protein with its N terminus on the cytoplasmic side and the C terminus in the lumen; if there are alternating series of insertion and stop transfer sequences within a single chain, the result is an integral membrane protein with multiple membrane spanning regions
      5. membrane proteins and secretory products are also glycosylated by the addition of oligosaccharide chains or conjugated to complex lipids in the endoplasmic reticulum and the Golgi apparatus – this is the way that a neuronal cell adhesion molecule (NCAM) is formed so that it may be anchored to the cell membrane
        1. in comparison, cytosolic proteins have little modification or processing compared to proteins that remain attached to the ER or Golgi apparatus
        2. in the Golgi complex the following occur: attachment of fatty acids, formation of O-linked surgard, sugar phosphorylation, sulfation of tyrosine residues
        3. in the endoplasmic reticulum, initiation of N-linked glycosylation begins
    4. axonal transport of membrane and secretory proteins in the neuron
      1. proteins move within the axon in three ways
        1. fast anterograde
          1. nearly all newly synthesized membranous organelles within axons are exported to the axon from the cell body by fast anterograde transport at a rate of 400 mm/day
            1. mitochondria use this system but because of their size get transported at around 50-100 mm/day
          2. fast anterograde transport is based on microtubules that provide a stationary track on which specific organelles move in a saltatory fashion
            1. NOTE: colchicines and vinblastine are alkaloids that cause the disruption of microtubules and block mitosis and interfere with fast anterograde transport
          3. motor molecule for anterograde movement is kinesin which look like little feet walking along the microtubules
        2. slow axoplasmic flow
          1. cytoskeletal elements and soluble proteins (cytosolic proteins) are transported down the axon by slow axoplasmic flow at a rate of 2.0 mm/day; these proteins form the neurofilaments and microtubules (composed of alpha and beta tubulin)
        3. fast retrograde
          1. returns materials from terminal to the cell body either for degradation or for restoration and reuse at a rate of 200 mm/day along microtubules with the motor molecule being dynein (retrograde transport)
            1. NOTE: herpes simplex, rabies, polio and tetanus toxin travel to the cell body this way; horseradish peroxidase, used in histochemical tracing, is transported this way
            2. Remember: kinesin down and dynein up
    5. fibrillar proteins of the cytoskeleton shape the neuron; these elements are in constant flux, adding and subtracting monomers to their length
      1. three fibrillar elements constitute the cytoskeleton
        1. microtubules
          1. the thickest of the neuron’s cytoskeletal fibers is constructed of 13 protofilaments; each monomer binds two GTP molecules or one GTP and one GDP molecule
          2. microtubule associated prteins (MAPs) regulate the stability of microtubules and promote their polymerization or assembly
        2. neurofilaments
          1. most abundant fibrillar components in axons are are the ‘bones’ of the cytoskeleton
          2. retain silver nitrate in staining
          3. in Alzheimer’s disease these proteins are modified and form a neurofibrillary tangle
        3. microfilaments
          1. smallest of the three types of proteins that make up the cytoskeleton
          2. polar polymers of globular actin monomers each bearing an ATP or ADP wound into a two stranded helix
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