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UNIT I

                                      Textbook of Medical Physiology, 11th Edition



                            ...
Organization of the Cell




           Figure 2-1

Copyright © 2006 by Elsevier, Inc.
Cell Composition

                              Water    ...70-85% of cell mass
                                Ions
     ...
Membrane Components:
                        LIPIDS:
                       • barrier to water and water-soluble substance...
Cell Membrane:
       Bilayer of Phospholipids with Proteins




              Figure 2-3

Copyright © 2006 by Elsevier, I...
Proteins:
       • provide “specificity” to a membrane
       • defined by mode of association with the lipid bilayer
    ...
Carbohydrates:
       • glycolipids (approx. 10%)
       • glycoproteins (majority of integral proteins)
       • proteogl...
Carbohydrates (Cont.):
       • negative charge of the carbo chains repels other
         negative charges
       • involv...
Cholesterol:
       • present in membranes in varying amounts
       • generally decreases membrane FLUIDITY and
         ...
Cell Organelles




                     Figure 2-2
Copyright © 2006 by Elsevier, Inc.
The Endoplasmic Reticulum:
       • Network of tubular and flat vesicular structures
       • Membrane is similar to (and ...
Rough or Granular ER
     • outer membrane surface
     covered with ribosomes

     • newly synthesized
     proteins are...
Smooth ER

      • site of lipid synthesis
              - phospholipids
              - cholesterol

      • growing ER m...
The Golgi Apparatus:

       • Membrane
       composition similar
       to that of the smooth
       ER and plasma
     ...
• Receives transport vesicles
  from smooth ER

  • Substances formed in the ER
  are “processed”
      - phosphorylated
 ...
Exocytosis:

      Secretory vesicles diffuse
      through the cytosol and
      fuse to the plasma
      membrane


    ...
Secretion:
 • secretory vesicles
 containing proteins
 synthesized in the RER bud
 from the Golgi apparatus

 • fuse with ...
Lysosomes:
       • vesicular organelle formed from budding Golgi

       • contain hydrolytic enzymes (acid hydrolases)
 ...
Lysosomal Storage Diseases

           Absence of one or more hydrolases
                   • not synthesized
            ...
Peroxisomes:

                          • similar physically to lysosomes

                          • two major differenc...
Secretory Granules




                                     Figure 2-6

Copyright © 2006 by Elsevier, Inc.
Mitochondria
       : Primary function: extraction of energy from nutrients




Copyright © 2006 by Elsevier, Inc.        ...
The Nucleus: “Control Center” of the Cell
                           The double nuclear membrane and matrix are
          ...
The nuclear membrane is permeated by
       thousands of nuclear pores



  • 100 nm in diameter

  • functional diameter
...
Chromatin (condensed DNA) is found in the nucleoplasm
       Nucleolus
          • one or more per nucleus
          • con...
Receptor-mediated endocytosis:

    • molecules attach to cell-
    surface receptors
    concentrated in clathrin-
    co...
Digestion of Substances in
       Pinocytotic or Phagocytic Vesicles




       Figure 2-12
Copyright © 2006 by Elsevier, ...
ATP production
Step 1.
• Carbohydrates are converted
  into glucose
• Proteins are converted into
  amino acids
• Fats are...
The Use of ATP for Cellular Function
• under “standard” conditions ∆G° is only -7.3 kcal/mole
• ATP concentration is ~10x ...
The Cytoskeleton
       Intermediate Filaments:
             • Comprised of cell-specific fibrillar monomers
             ...
Cilia and Ciliary Movements:
     • Occurs only on the inside surfaces
       of the human airway and fallopian
       tub...
Ameboid Locomotion:
       • continual endocytosis at the “tail”and exocytosis at the leading edge of
       the pseudopod...
Cell movement is influenced by
     chemical substances…




                                     Chemotaxis

     Low con...
UNIT I

                                      Textbook of Medical Physiology, 11th Edition



                            ...
Central Dogma of Molecular Biology


                                          DNA (genes)

                              ...
Transcription:




           Figure 3-7

Copyright © 2006 by Elsevier, Inc.
Overview:
       Step 1. RNA polymerase binds to the promoter sequence.
       Step 2. The RNA polymerase temporarily “unw...
Messenger RNA:
      • complementary in sequence to the DNA coding strand

      • 100’s to 1000’s of nucleotides per stra...
The Process of
                                                            Translation
           nuclear                 ...
Transfer RNA
    • acts as a carrier molecule during protein synthesis
    • each transfer RNA (tRNA) combines with one AA...
Ribosomes
       Polyribosomes: multiple ribosomes can simultaneously
       translate a single mRNA




                 ...
Chemical Events in Protein Formation




    Figure 3-11
Copyright © 2006 by Elsevier, Inc.
Overview :Protein Formation
       Phase 1: Initiation

       • small ribosomal subunit and initiator tRNA (Met)
        ...
Overview :Protein Formation
       Phase 2: Elongation
       • AA-tRNA binds to the ribosomal A-site

       • peptidyl t...
Overview :Protein Formation
       Phase 3: Termination

       • Release factor binds to the stop codon.

       • Comple...
Control of Genetic Function
 and Biochemical Activity



                                          DNA (genes)         tra...
Genomics


                 Genomics: the large-scale study of
                 the genome


              • Recent estima...
identify a gene

                                     determine nucleic acid sequence
                                    ...
Proteomics

                          Proteomics: the large-scale analysis of
                          proteins (i.e. the...
Transcriptional Control:
                                 The Operon: a procaryote model
 • series of
   genes and
   thei...
Negative Regulation

       • sequences called “repressor operators” bind repressor
       proteins

       • binding inte...
Positive Regulation

       • so-called “activator operators” bind activator
       proteins

       • binding facilitates...
Genetic Control of Cell Reproduction


    Life Cycle of the Cell:

                                 M
                   ...
DNA Replication: S phase
       • switched on by the cytoplasmic S-phase activator

       • Replication is initiated at r...
DNA Replication: S phase
       • nucleotides are always added to the 3’ end
             (DNA and RNA)

       • formatio...
Chromosomes and Their Replication

      • “New” DNA helices associate with histones to form
      chromosomes

      • Th...
Stages of Cell Reproduction

                                                   Mitosis: M phase

                        ...
Control of Cell Growth

                        What determines the rate of cell growth?
                                 ...
Cell Differentiation

       Different from reproduction ...
       • changes in physical and functional properties of
   ...
Cancer

                                     Dysregulation of cell growth

              Caused in all or almost all cases...
What causes these mutations?

       • Ionizing radiation: disrupts DNA strands

       • Chemicals: “carcinogens”

      ...
Q: Why does cancer kill?


                             A: Cancer cells compete
                                successful...
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  1. 1. UNIT I Textbook of Medical Physiology, 11th Edition Chapter 2: The Cell and its Functions Slides by John E. Hall, Ph.D. and Louise C. Nuttle, Ph.D. GUYTON & HALL Copyright © 2006 by Elsevier, Inc.
  2. 2. Organization of the Cell Figure 2-1 Copyright © 2006 by Elsevier, Inc.
  3. 3. Cell Composition Water ...70-85% of cell mass Ions Proteins ...10-20% Lipids ...2-95% Carbohydrates ...1-6% Copyright © 2006 by Elsevier, Inc.
  4. 4. Membrane Components: LIPIDS: • barrier to water and water-soluble substances • organized in a bilayer of phospholipid molecules CO2 N2 O2 ions glucose H2O urea halothane hydrophilic “head” hydrophobic FA “tail” Copyright © 2006 by Elsevier, Inc.
  5. 5. Cell Membrane: Bilayer of Phospholipids with Proteins Figure 2-3 Copyright © 2006 by Elsevier, Inc.
  6. 6. Proteins: • provide “specificity” to a membrane • defined by mode of association with the lipid bilayer – integral: channels, pores, carriers, enzymes, etc. – peripheral: enzymes, intracellular signal mediators K+ Copyright © 2006 by Elsevier, Inc.
  7. 7. Carbohydrates: • glycolipids (approx. 10%) • glycoproteins (majority of integral proteins) • proteoglycans GLYCOCALYX Copyright © 2006 by Elsevier, Inc.
  8. 8. Carbohydrates (Cont.): • negative charge of the carbo chains repels other negative charges • involved in cell-cell attachments/interactions • play a role in immune reactions (-) (-) (-) (-) (-) GLYCOCALYX (-) (-) Copyright © 2006 by Elsevier, Inc.
  9. 9. Cholesterol: • present in membranes in varying amounts • generally decreases membrane FLUIDITY and PERMEABILITY (except in plasma membrane) • increases membrane FLEXIBILITY and STABILITY (-) (-) (-) (-) (-) (-) (-) Copyright © 2006 by Elsevier, Inc.
  10. 10. Cell Organelles Figure 2-2 Copyright © 2006 by Elsevier, Inc.
  11. 11. The Endoplasmic Reticulum: • Network of tubular and flat vesicular structures • Membrane is similar to (and contiguous with) the plasma membrane • Space inside the tubules is called the endoplasmic matrix Figure 2-4 Copyright © 2006 by Elsevier, Inc.
  12. 12. Rough or Granular ER • outer membrane surface covered with ribosomes • newly synthesized proteins are extruded into the ER matrix • proteins are “processed” inside the matrix - crosslinked - folded - glycosylated (N-linked) - cleaved Figure 2-13 Copyright © 2006 by Elsevier, Inc.
  13. 13. Smooth ER • site of lipid synthesis - phospholipids - cholesterol • growing ER membrane buds continuously forming transport vesicles, most of which migrate to the Golgi apparatus Figure 2-13 Copyright © 2006 by Elsevier, Inc.
  14. 14. The Golgi Apparatus: • Membrane composition similar to that of the smooth ER and plasma membrane • Composed of 4 or more stacked layers of flat vesicular structures Figure 2-5 Copyright © 2006 by Elsevier, Inc.
  15. 15. • Receives transport vesicles from smooth ER • Substances formed in the ER are “processed” - phosphorylated - glycosylated • Substances are concentrated, sorted and packaged for secretion. Copyright © 2006 by Elsevier, Inc.
  16. 16. Exocytosis: Secretory vesicles diffuse through the cytosol and fuse to the plasma membrane Lysosomes fuse with internal endocytotic vesicles Copyright © 2006 by Elsevier, Inc.
  17. 17. Secretion: • secretory vesicles containing proteins synthesized in the RER bud from the Golgi apparatus • fuse with plasma membrane to release contents - constitutive secretion - happens randomly - stimulated secretion - requires trigger Copyright © 2006 by Elsevier, Inc.
  18. 18. Lysosomes: • vesicular organelle formed from budding Golgi • contain hydrolytic enzymes (acid hydrolases) - phosphatases - nucleases - proteases - lipid-degrading enzymes - lysozymes digest bacteria • fuse with pinocytotic or phagocytotic vesicles to form digestive vesicles Figure 2-12 Copyright © 2006 by Elsevier, Inc.
  19. 19. Lysosomal Storage Diseases Absence of one or more hydrolases • not synthesized • inactive • not properly sorted and packaged Result: Lysosomes become engorged with undigested substrate Examples: • Acid lipase A deficiency • I-cell disease (non-specific) • Tay-Sachs disease (HEX A) Copyright © 2006 by Elsevier, Inc.
  20. 20. Peroxisomes: • similar physically to lysosomes • two major differences: • formed by self-replication • they contain oxidases Function: oxidize substances (e.g. alcohol) that may be otherwise poisonous Copyright © 2006 by Elsevier, Inc.
  21. 21. Secretory Granules Figure 2-6 Copyright © 2006 by Elsevier, Inc.
  22. 22. Mitochondria : Primary function: extraction of energy from nutrients Copyright © 2006 by Elsevier, Inc. Figure 2-7
  23. 23. The Nucleus: “Control Center” of the Cell The double nuclear membrane and matrix are contiguous with the endoplasmic reticulum Copyright © 2006 by Elsevier, Inc. Figure 2-9
  24. 24. The nuclear membrane is permeated by thousands of nuclear pores • 100 nm in diameter • functional diameter is ~9 nm • (selectively) permeable to molecules of up to 44,000 MW Figure 2-9 Copyright © 2006 by Elsevier, Inc.
  25. 25. Chromatin (condensed DNA) is found in the nucleoplasm Nucleolus • one or more per nucleus • contains RNA and proteins • not membrane delimited • functions to form the granular “subunits” of ribosomes Copyright © 2006 by Elsevier, Inc.
  26. 26. Receptor-mediated endocytosis: • molecules attach to cell- surface receptors concentrated in clathrin- coated pits • receptor binding induces invagination • also ATP-dependent and involves recruitment of actin and myosin Figure 2-11 Copyright © 2006 by Elsevier, Inc.
  27. 27. Digestion of Substances in Pinocytotic or Phagocytic Vesicles Figure 2-12 Copyright © 2006 by Elsevier, Inc.
  28. 28. ATP production Step 1. • Carbohydrates are converted into glucose • Proteins are converted into amino acids • Fats are converted into fatty acids Step 2. • Glucose, AA, and FA are processed into AcetylCoA Step 3. A maximum of 38 molecules of • AcetylCoA reacts with O2 to ATP are formed per molecule of produce ATP glucose degraded. (More in Chapter 67)
  29. 29. The Use of ATP for Cellular Function • under “standard” conditions ∆G° is only -7.3 kcal/mole • ATP concentration is ~10x that of ADP, the ∆G is -12 kcal/mole 1. Membrane transport 2. Synthesis of chemical compounds 3. Mechanical work Figure 2-15
  30. 30. The Cytoskeleton Intermediate Filaments: • Comprised of cell-specific fibrillar monomers (e.g. vimentin, neurofilament proteins, keratins, nuclear lamins) Microtubules: • Heterodimers of α and β tubulin • Make up spindle fibers, core of axoneme structure Thin Filaments: • F-Actin • Make up “stress fibers” in non-muscle cells Thick Filaments: • Myosin (types I and II) • Together with actin support cellular locomotion and subcellular transport Copyright © 2006 by Elsevier, Inc.
  31. 31. Cilia and Ciliary Movements: • Occurs only on the inside surfaces of the human airway and fallopian tubes • Each cilium is comprised of 11 microtubules • 9 double tubules • 2 single tubules axoneme • Each cilium is an outgrowth of the basal body and is covered by an outcropping of the plasma membrane. • Ciliary movement is ATP-dependent (also requires Ca2+ and Mg2+) Figure 2-17 Copyright © 2006 by Elsevier, Inc.
  32. 32. Ameboid Locomotion: • continual endocytosis at the “tail”and exocytosis at the leading edge of the pseudopodium • attachment of the pseudopodium is facilitated by receptor proteins carried by vesicles • forward movement results through interaction of actin and myosin (ATP-dependent) Copyright © 2006 by Elsevier, Inc. Figure 2-16
  33. 33. Cell movement is influenced by chemical substances… Chemotaxis Low concentration high concentration (negative) (positive) Copyright © 2006 by Elsevier, Inc.
  34. 34. UNIT I Textbook of Medical Physiology, 11th Edition Chapter 3: Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction Slides by John E. Hall, Ph.D. and Louise C. Nuttle, Ph.D. GUYTON & HALL Copyright © 2006 by Elsevier, Inc.
  35. 35. Central Dogma of Molecular Biology DNA (genes) RNA Proteins Structural Enzymes Cell function Figure 3-2 Copyright © 2006 by Elsevier, Inc.
  36. 36. Transcription: Figure 3-7 Copyright © 2006 by Elsevier, Inc.
  37. 37. Overview: Step 1. RNA polymerase binds to the promoter sequence. Step 2. The RNA polymerase temporarily “unwinds” the DNA double helix. Step 3. The polymerase “reads” the DNA strand and adds complementary RNA molecules to the DNA template. Step 4. “Activated” RNA molecules react with the growing end of the RNA strand and are added (3’ end). Step 5. Transcription ends when the RNA polymerase reaches a chain terminating sequence, releasing both the polymerase and the RNA strand. Copyright © 2006 by Elsevier, Inc.
  38. 38. Messenger RNA: • complementary in sequence to the DNA coding strand • 100’s to 1000’s of nucleotides per strand • organized in codons - triplet bases - each codon “codes” for one amino acid (AA) - each AA - except met- is coded for by multiple codons - start codon: AUG (specific for met) - stop codons: UAA, UAG, UGA Copyright © 2006 by Elsevier, Inc.
  39. 39. The Process of Translation nuclear plasma envelope membrane NUCLEUS DNA (genes) DNA DNA TRANSCRIPTION RNA RNA RNA SPLICING Proteins RNA TRANSPORT Structural Enzymes TRANSLATION OF ribosomes MESSENGER RNA protein Cell function CYTOSOL Copyright © 2006 by Elsevier, Inc.
  40. 40. Transfer RNA • acts as a carrier molecule during protein synthesis • each transfer RNA (tRNA) combines with one AA • each tRNA recognizes a specific codon by way of a complementary anticodon on the tRNA molecule Figure 3-9 Copyright © 2006 by Elsevier, Inc.
  41. 41. Ribosomes Polyribosomes: multiple ribosomes can simultaneously translate a single mRNA Figure 3-11 Copyright © 2006 by Elsevier, Inc.
  42. 42. Chemical Events in Protein Formation Figure 3-11 Copyright © 2006 by Elsevier, Inc.
  43. 43. Overview :Protein Formation Phase 1: Initiation • small ribosomal subunit and initiator tRNA (Met) complex binds to 5’end of an mRNA chain • this complex moves along mRNA molecule until it encounters a start codon (AUG) • initiation factors dissociate and large ribosomal subunit binds Copyright © 2006 by Elsevier, Inc.
  44. 44. Overview :Protein Formation Phase 2: Elongation • AA-tRNA binds to the ribosomal A-site • peptidyl transferase joins the tRNA at the P-site to the AA linked to the tRNA at the A-site with a peptide bond • the new peptidyl-tRNA is translocated from the A-site to the P-site Copyright © 2006 by Elsevier, Inc.
  45. 45. Overview :Protein Formation Phase 3: Termination • Release factor binds to the stop codon. • Completed polypeptide is released. • Ribosome dissociates into its 2 subunits. Copyright © 2006 by Elsevier, Inc.
  46. 46. Control of Genetic Function and Biochemical Activity DNA (genes) transcription processing transport to cytosol RNA translation mRNA stability Proteins Structural Enzymes protein activity Cell function Copyright © 2006 by Elsevier, Inc.
  47. 47. Genomics Genomics: the large-scale study of the genome • Recent estimates suggest ~ 30,000 genes • Humans are 99.8% identical at the genome level, 99.999% identical in the coding regions Copyright © 2006 by Elsevier, Inc.
  48. 48. identify a gene determine nucleic acid sequence (sequence homology?) Bioinformatics determine amino acid sequence (fold homology?) best guess... Copyright © 2006 by Elsevier, Inc.
  49. 49. Proteomics Proteomics: the large-scale analysis of proteins (i.e. the proteome) • “Proteome” describes the protein composition of a cell • approximately 10,000 proteins per cell, or ~15% of total possible gene products Genome ≠ Proteome Copyright © 2006 by Elsevier, Inc.
  50. 50. Transcriptional Control: The Operon: a procaryote model • series of genes and their shared regulatory elements • gene products contribute to a common process Figure 3-12 Copyright © 2006 by Elsevier, Inc.
  51. 51. Negative Regulation • sequences called “repressor operators” bind repressor proteins • binding interferes with the ability of the RNA polymerase to bind to the promoter NO TRANSCRIPTION Copyright © 2006 by Elsevier, Inc.
  52. 52. Positive Regulation • so-called “activator operators” bind activator proteins • binding facilitates the association of the RNA polymerase with the promoter ENHANCED TRANSCRIPTION Copyright © 2006 by Elsevier, Inc.
  53. 53. Genetic Control of Cell Reproduction Life Cycle of the Cell: M M phase: (mitosis) • mitosis G2 • cytokinesis (Gap 2) G1 (Gap 1) EUKARYOTIC Interphase (>95%): CELL CYCLE Cells that • G1 phase cease • S phase (DNA synthesis) division • G2 phase S phase (DNA synthesis) Copyright © 2006 by Elsevier, Inc.
  54. 54. DNA Replication: S phase • switched on by the cytoplasmic S-phase activator • Replication is initiated at replication origin and proceeds in both directions. • Entire genome is replicated once - further replication is blocked • involves DNA polymerase and other proteins that function to unwind and stabilize the DNA and “prime” DNA replication of the “lagging” strand. Copyright © 2006 by Elsevier, Inc.
  55. 55. DNA Replication: S phase • nucleotides are always added to the 3’ end (DNA and RNA) • formation of Okazaki fragments on lagging strand • “new” DNA is proofread by DNA polymerase • repairs are made and gaps filled by DNA ligase Copyright © 2006 by Elsevier, Inc.
  56. 56. Chromosomes and Their Replication • “New” DNA helices associate with histones to form chromosomes • The two chromosomes remain temporarily attached at the centromere. • Together, these chromosomes are called chromatids. Copyright © 2006 by Elsevier, Inc.
  57. 57. Stages of Cell Reproduction Mitosis: M phase 1. Assembly of the mitotic apparatus 2. Prophase (A,B,C) 3. Prometaphase (D) 4. Metaphase (E) 5. Anaphase (F) 6. Telophase (G, H) Copyright © 2006 by Elsevier, Inc. Figure 3-13
  58. 58. Control of Cell Growth What determines the rate of cell growth? • growth factors • contact inhibition • cellular secretions (negative feedback) RAPID: bone marrow, skin, intestinal epithelia SLOW/NEVER: smooth muscle, neurons, striated muscle Copyright © 2006 by Elsevier, Inc.
  59. 59. Cell Differentiation Different from reproduction ... • changes in physical and functional properties of cells as they proliferate • results not from the loss of genes but from the selective repression/expression of specific genes • development occurs in large part as a result of “inductions,” one part of the body affecting another Copyright © 2006 by Elsevier, Inc.
  60. 60. Cancer Dysregulation of cell growth Caused in all or almost all cases by the mutation or abnormal activation of genes that encode proteins that control cell growth and/or mitosis • Proto-oncogenes: the “normal” genes • Oncogenes: the “abnormal” gene • Antioncogenes: genes whose product suppress the activation of oncogenes Not all mutations lead to cancer! Copyright © 2006 by Elsevier, Inc.
  61. 61. What causes these mutations? • Ionizing radiation: disrupts DNA strands • Chemicals: “carcinogens” • Physical irritants: e.g., abrasion of the intestinal lining • Hereditary “tendencies”: e.g., some breast cancer • Viruses: so-called “tumor viruses” (particularly retroviruses) Copyright © 2006 by Elsevier, Inc.
  62. 62. Q: Why does cancer kill? A: Cancer cells compete successfully with normal cells for limited nutrients Copyright © 2006 by Elsevier, Inc.
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