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Cellular Physiology – Dr. Anita Woods.docx

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Physiology 3140A
Donglin Bai

Cellular Physiology – Dr. Anita Woods Introduction • Average cell o Why are drawings of the average cell misleading?  Lipid bilayer are not present  Cell is not a bag of cytoplasm – there are proteins, RNA & cytoskeleton  Villi are not present  Receptors are not present  Organelle numbers are incorrect  Packed environment o Issues with communication  Solved by compartmentalization (membranes), guided signaling and micro-domains of signaling • Molecules in 2D plane to communicate (guided) • Tether proteins to specific components of cytoskeleton (actin) (micro-domains) • Lipid raft – proteins within raft (restricted) • Similarities of most cells o Cells contain DNA (most – RBC is the exception) o Cells require energy  High demand energy processes: • High-fidelity replication of DNA • Separation of DNA strands for replication • Production of RNA & proteins (tRNA, mRNA, rRNA, snRNA, siRNA & xRNA) o Cells function as biochemical factories  Cells have to manipulate similar collection of small molecules: sugars, nucleotides & AA  All cells require ATP as building block for synthesizing DNA & RNA  One factory to make multiple things o Cells are enclosed in a plasma membrane  Selective barrier  Communication  Dynamic & physiologically active • Differences of most cells o Variation in cell shape  External and internal cues change cytoskeleton (especially actin) = change in shape  Composition of lipids in bilayer affect shape o Organelle number  Some cells are multinuclear & others have no nucleus  Cell requiring more energy = more mitochondria  Cell requiring more protein = more RER o Ability to express parts of their genome  Differentiation of cells causes “turning-on or turning-off” genes • Membrane proteins o Each cell will translate a different set of membrane proteins  Proteins for cell-matrix interactions/adhesions  Proteins for cell-cell junctions  Intracellular proteins that impart shape & strength  Proteins are receptors for cell-signaling Integrating Cells Into Tissues • Cell differentiation o Selective gene expression is employed in differentiated cells o Control how much the cell type will proliferate, when it will specialize & how it will specialize, what it will interact with & how it will move • Cell memory o Genes expressed depend on the cell’s past as well as their present o Record of signals their ancestors received during embryonic development • Epigenetics • Different cell types work together to form structures that achieve a common function: tissues • Tissues work together • Five Classes of Tissues o Nervous tissue  Brain, spinal cord, neuron & glial cells o Muscular tissue  Muscle, cardiac muscle, smooth muscle, skeletal muscle o Connective tissue  Collagen based (bones, teeth, cartilage, tendons) & fat o Epithelial tissue  Lines body surfaces  Blood vessel cells, alveoli, gut lining & epidermis o Blood  White blood cells, red blood cells, platelets & plasma Germ Cell Layer Development – Gastrulation • Basic machinery of embryonic development is essentially the same in vertebrates & invertebrates • Single cell fertilized embryo, cells proliferate rapidly & cells begin to organize into differentiated cells that will become the whole organism • Formation of animal requires that many types of tissues be developed Germ Layers • Ectoderm o Exterior of embryo o Precursor to epidermis & nervous system (neurons) • Endoderm o Interior of embryo o Precursor to gut & its appendages (lungs & liver) o Alveolar cells, thyroid cells & pancreatic cells • Mesoderm o Cells in between two layers o Precursor to muscles & connective tissues o Cardiac muscle (single-nuclei & striated – connected via intercalated disc (gap junctions & anchoring adhesions), skeletal muscle (multi-nucleated & striated – long fibrous cells), tubule cells, red blood cells & smooth muscle (single-nuclei, non-striated (no sarcomeres) – most are connected via gap junctions) Cell-Matrix Interactions • Extracellular matrix (ECM) o Important network of secreted macromolecules that has many functions:  Helps to hold cells & tissues together • Joints (muscle, tendon & bone) • Skin  Provides an organized environment where migratory cells can move & interact with one another in orderly ways • Prevents escape  Provides information to the cell (bidirectional transfer of information) which regulates cell proliferation, differentiation & survival o Complex meshwork of proteins & polysaccharides that are secreted by cells into the spaces around them o Ability of cells to sense environment & ability of matrix to give information - essential process Epithelial Tissue Connective Tissue Extracellular matrix is rare (mostly cellular) Extracellular matrix is plentiful (very few cells) Existing matrix is called basal lamina Matrix is rich in collagen with proteoglycans Cells attach to each other by cell-cell adhesions Cells sparsely distributed in matrix Cells tightly bound into sheets called epithelia Direct attachment between cells is rare Cell-cell adhesions bears most of mechanical Matrix bears most of the stress & not the cells stress • Anchoring junctions o Connect cells to extracellular matrix o Both use integrins o Focal Adhesions  Actin filaments  integrins  matrix  Transient (aren’t as strong) o Hemidesmosomes  Intermediate filaments  integrins  matrix  Strong interactions • Adaptor proteins o Ex. Signals from ECM transduced to nucleus via connections to skeletal proteins of nucleus: lamins Case Study: Human Connective Tissue Diseases • Most common: osteoarthritis o Affecting both cartilage and underlying bone o Not a normal process of aging o Enzymes break down of broken cartilage and collagen is excessive & inappropriate o Proteoglycans becomes less glycosylated, cushion is lost – dry and rigid Components of Cell-Matrix Collagen  More than 20 types of collagen proteins in the human genome (34 genes contribute)  Insoluble & trimeric (homotrimeric or heterotrimeric)  Basic collagen structure o Triple-helix characteristic repeating motif of Glycine-X-Y (X & Y can be any amino- acid but are usually proline & hydroxyproline) o Glycine (small) wraps around X & Y to form a helix o One collagen has 3 peptides o Globular (blob) N-terminal & C-terminal domains are usually removed prior to formation of mature collagen chain  Differences are observed in tissue distribution & type of matrix due to o Number of helix repeats i.e. length of triple helix portion of collagen o Interrupting segments within the helix portion & shape of the globular C & N terminal domains  Amino acids that aren’t glycine, proline or hydroxyproline – makes a bulge o Covalent modifications to triple helix  Aldehyde groups, hydroxyl groups  Amino acid sequence determines what groups are added  Biosynthesis o Polypeptide chains are made & post-translationally modified: hydroxylation & glycosylation to proline and lysine o Makes triple helix that wind together to make fibril o Add oligosaccharide o N & C globular domains are cut off o Aggregate together Type Structural Feature Representative Tissue I Fibrillar, heterotrimeric Skin, bone (most abundant in), ligaments II Fibrillar, homotrimeric Cartilage, vitreous humour IV Sheet-forming, heterotrimeriBasal lamina VI Fibril-associated, heterotriSkeletal muscle Lateral association with type I collagen XIII Transmembrane & homotrimericHemidesmosomes in skin • Categorization of Collagens o Fibrillar Collagens  Most abundant  Aggregate into fibres (organized)  Provide mechanical support to bone, tendons & teeth o Sheet-Forming Collagens  Form sheets (2D structure)  Meshwork  Basil lamina (anchor tissue for epithelial cell) ‘  Important for strength & filtering o Fibril-Association Collagens  Link fibrillar collagens together & with other things  Makes a bridge o Transmembrane Collagens  Passes through membrane  Sticks out into matrix to be: anchors or receptors Type of Collagen Disorder I • Mutation: osteogenesis imperfecta (brittle bone) • Disruption in triple helix formation – unstable collagen fibres Straight fibres • Amino acid bulges will prevent fibrils to associate causing gaps • Affects mineralization of bone (overmineralized = bad) • Affects skin  becomes thin & bruises easily II • Mutation: Achondroplaysia: Stickler’s Syndrome (dwarfism) • Long bone formation: bones begin with cartilage  replaced by bone over the years Meshwork • Shortened limbs, malformed bones & lack of bone formation • Vision issues (vitreous humour) IV • Mutation: Alport’s Syndrome • Renal dysfunction Found near • 2 layers of basal lamina in glomeruli of nephrons are abnormal epithelial cells o Meshwork becomes inefficient o Proteins, RBC & WBC gets into urine & inflames basal lamina VI • Mutation: Ulrich’s Congenital Muscular Dystrophy • Muscle weakness Linker for type I • Results from improper muscle attachment to ECM • Stress causes shearing & disattachment Proteoglycans • Proteins have one or more specialized sugar attached to it (glycoprotein) • Glycosaminoglycans (GAGs) are specialized polysaccharides (repeating disaccharide) that are covalently linked to the protein core to form the proteoglycan • Highly charged due to GAG side chains – overall negative charge • Functions to provide cushion (due to water-loving properties) & this ability will vary depending on o Type of proteoglycan core o Number of GAG side chains o Whether or not macromolecules are secreted or cell surface associated • Synthesis o Protein core is made in RER o GAG chains are added to protein core in golgi apparatus o Multistep enzymatic reaction  First xylose is added to serine residues  Add 2 galactoses – add repeating disaccharides  Add sulphate – lots of negative charge • Likes water (longer=more water loving = more cushion) • Glycosaminoglycans – all cushion of ECM, all sulphated o Chondroitin sulphate o Keratan sulphate o Heparin sulphate o Hyaluronate (found in blood  role in signaling) • Large diversity of proteoglycans – most common: o Perlecan – highly expressed in basal lamina o Aggrecan – highly expressed in cartilage Multiadhesive Matrix Proteins • Bind cell-surface adhesion receptors • Long flexible molecules • Contain domains that can bind to a variety of things (collagen, polysaccharides, cell surface receptors, growth factors & hormones) – glycosylated • Ex. Fibronectin o Type of multi-adhesive matrix proteins o One gene but splicing differences make multiple isoforms o 2 major forms: soluble (plasma) & insoluble (ECM) o Stretching soluble fibronectin transforms it into insoluble form o Made of many cell types o Important in wound healing (blot clotting), migration & differentiation of cells o Help cells attach to other ECM components • Ex. laminin Integrins • Signal between cells & their environment • Bridge between ECM & cytoskeleton – function as adhesive receptors • Binds the matrix as heterodimers (18 α & 8 β subunits – 24 α & β unique pairs) • Combination of heterodimers determines which matrix component they can bind to: o Outside-in-signaling  Transduction of information to nucleus of cell via. activation of cell signaling cascades o Inside-out-signaling  Integrins cytoplasmic side will change ECM domain so it can interact or not Known Integrin Heterodimers Integrin Subunits Ligand Cell-Type Distribution α1β1 Collagen Multiple cells α3β1 Laminin Multiple cells α5β1 Fibronectin Fibroblasts (wound healing & cell migration) α6β4 Laminin Epithelial cells **No research on integrins binding to proteoglycans Case Study: Epidermolysis Bullosa • Integrin mutation: α6 mutation • Skin blistering & fragility • Laminin Cell-Cell Interactions Cell-Cell Adhesions • Many tissue types rely on tight cell-to-cell adhesions in order to function (epithelial tissues that line the gastrointestinal tract, epithelial cells of nephrons) • Some of these adhesions adhere cells together tightly & others are loosely bound • Cells of same type can bind to each other or cells from various tissue types can bind to each other to form complex structures • Properties affecting cell-cell adhesion strength o Binding affinity of interacting molecules  How well they are attached to each other o Spatial distribution of interacting molecules  More adhesion molecules in cell membranes = interactions are stronger o Activity state of adhesion molecules  Active = tight interaction o External forces surrounding the cells  Pressure will stimulate a tighter interaction Cell-Cell Junction Types • Anchoring junctions o Use cadherins as adhesion molecule o Desmosome  Intermediate filaments  Stronger interaction o Adherens junction  Actin filaments  Weaker interaction • Occluding junctions (Tight junctions) o Seal polarized epithelial cells - provide a barrier function in the body o Ex. cells lining the small intestine, tubules of the kidney & blood-brain barrier o Can be altered to cause leakiness between cells  allows for paracellular transport o Intracellular signaling pathways can change the leakiness of a tight junction depending on the requirements of the specific tissue type o Use different adhesion molecules: occluding & claudin • Communicating junctions o Mediates passage of chemical or electrical signals from one interacting cell to its partners through gap junction or chemical synapse o Use different molecules: connexins or pannexins Cell-Cell Interactions • Lateral (aka cis) interactions o Cell adhesion molecules expressed on one cell will interact laterally through either extracellular domains, cytosolic domains or both as homodimers or oligodimers o Tight interaction within a cell • Intracellular (aka trans) inte
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