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CHAPTER 3 The Cellular Level of Organization INTRODUCTION • A cell = basic living, structural, & functional unit of body • Cytology = study of cell structure • Cell physiology = study of cell function • Generalized view of cell = composite of many different cells • No single cell includes all of the features seen in the generalized cell. PARTS of a CELL • Cell can be divided into three principal parts: – Plasma (cell) membrane (PM) – Cytoplasm • Cytosol • Organelles (except for the nucleus) – Nucleus THE PLASMA MEMBRANE • Flexible, sturdy barrier surrounding cytoplasm of cell • Fluid mosaic model (Figure 3.2) – “Proteins in a sea of lipids” – Lipid bilayer (amphipathic) • two back-to-back layers of PL molecules – FA tail region = NONpolar (hydrophobic) – PO4-3 head region = polar (hydrophilic) • cholesterol • glycolipids – glyco = “sugar” – extracellular face only Arrangement of Membrane Proteins • Integral proteins – amphipathic – anchored w/in membrane • Peripheral proteins – associated w/ head of PL or w/ integral protein – can be removed from membrane – glycoproteins • CHO groups protrude into ECF • glycocalyx Functions of Membrane Proteins • Ion channels (integral) • Transporters (integral • Receptors (integral) • Enzymes (integral or peripheral) • Cell identity marker (glycoprotein) • Linkers (integral and peripheral) Membrane Fluidity • “Mobility with structure” – movement w/in bilayer – no flip-flop • Dependent upon: – # of double bonds in fatty acid tails of lipids – amount of cholesterol present • stabilizes membrane • reduces fluidity @ normal body temp. • Allows self-repair of lipid bilayer • Enables many cellular processes – assembly of membrane proteins – cell movement, growth, etc. Membrane Permeability • Selective permeability – Permeable to small, nonpolar, uncharged molecules – Permeable to water – Impermeable to ions & charged or polar molecules • Increased by transmembrane proteins • Macromolecules must cross PM via vesicular transport. Gradients Across PM • Difference in concentration of a chemical or electrical charge between opposite sides of PM – Concentration gradient – Electrical gradient – Electrochemical gradient • Allow for movement of substances across PM – “downhill” movement • Oxygen & Na+ more concentrated outside cell • CO2 & K+ more concentrated inside cell TRANSPORT ACROSS PM • “Downhill” movement is passive – Diffusion thru lipid bilayer – Diffusion thru ion channels – Facilitated diffusion • Requires transporter (usually a protein) • “Uphill” movement is “active” – Requires cellular energy in form of ATP • Substances can also enter or leave cell thru vesicle transport Principles of Diffusion • Diffusion = random mixing of particles that occurs in a solution as a result of the kinetic energy of the particles • Occurs down concentration gradient • Equilibrium eventually achieved • Diffusion rate influenced by : – Steepness of the concentration gradient – Temperature – Size or mass of the diffusing substance – Surface area – Diffusion distance Diffusion Through Lipid Bilayer • Nonpolar, hydrophobic molecules diffuse freely – respiratory gases – lipids – small alcohols – ammonia • Important for gas exchange, absorption of some nutrients, & excretion of some wastes Diffusion Thru Membrane Channels • Most are ion channels – small, inorganic (hydrophilic) ions • Ion channels are selective – gated or open all the time – slower than free diffusion because site specific Osmosis • Water molecules penetrate membrane via diffusion – through lipid bilayer – through aquaporins • transmembrane proteins that function as water channels • Water moves from an area of lower solute concentration to an area of higher solute concentration. • Occurs only when membrane is permeable to water but not to certain solutes Osmotic Pressure • Force exerted on membrane by impermeable solute • Proportional to [solute] that cannot cross membrane Tonicity • Measure of solution’s ability to change volume of cells by altering their water concentration • Isotonic solution – [solute] is same on both sides of PM – RBCs maintain normal shape (Fig. 3.7a) • Hypotonic solution – [solute] in sol’n lower than inside cell (cytosol) – Water flows into cell to equalize [solute] – RBCs undergo hemolysis (Fig. 3.7b) • Hypertonic solution – [solute] in sol’n higher than inside cell (cytosol) – Water flows out of cell to equalize [solute] – RBCs undergo crenation (Fig. 3.7c) Facilitated Diffusion • Transport of highly charged or polar solutes across PM • Solute binds to specific transporter – Transporter undergoes a conformational change – Solute carried from one side of PM to other • Saturable process – Transport maximum – Rate of facilitated diffusion dependent upon: • steepness of concentration gradient • # of transporter proteins available • Transport of glucose, urea, fructose, galactose, & some vitamins • **PASSIVE process!! Facilitated Diffusion of Glucose • Glucose binds transport protein • Transport protein Δ shape • Glc moves across PM (down concentration gradient) • Kinase enzyme reduces [glc] inside cell – glc-6-P unusable by cell • Transporter proteins always bring glucose into cell Active Transport • Moves solutes AGAINST concentration gradient • Requires energy – ATP (primary) – Ion concentration gradient (secondary) • Saturable process • Ex: Na+/K+ pump (Fig 3.8) Primary Active Transport • Na+/K+ pump most prevalent (Figure 3.8) – Energy derived from ATP hydrolysis – Maintains low [Na+] and high [K+] in cytosol • 3 Na+ bind transporter (intracellular side of PM) • ATP hydrolysis causes conformational change & release of Na+ to ECF • 2 K+ bind & cause release of Pi to cytosol • Conformational change & 2 K+ released in cytosol Secondary Active Transport • Energy stored in Na+ or H+ concentration gradient drives other substances against own gradients • Indirect use of ATP • Digitalis slows Na+/Ca+2 ion antiporters – allows more Ca+2 to stay inside heart muscle cells • increases force of contraction strengthens heartbeat Transport in Vesicles • Invaginations of PM enclose substances & transport into or out of cell – Endocytosis = bringing something into cell – Exocytosis = release of something from cell • Vesicular transport is an active process Vesicular Transport--Endocytosis • Receptor-mediated endocytosis = selective uptake of large molecules/particles by cells – Ex: internalization of LDL particles • Phagocytosis = macrophages & neutrophils engulf large particles – Particle binds to receptor protein on PM & is surrounded by pseudopods – Disposal of microbes, old cells, etc. • Pinocytosis (bulk-phase endocytosis) = cell drinking – No receptor proteins Vesicular Transport--Exocytosis • Exocytosis – Vesicle formation inside cell – Vesicle fuses w/ cell membrane – Vesicle products released from cell • digestive enzymes, hormones, NT, wastes – Replace/recycle cell membrane lost during endocytosis CYTOPLASM • Cytosol = the semifluid portion of cytoplasm that contains inclusions and dissolved solutes • Organelles = specialized structures that perform specific functions in cellular growth, maintenance, and repro. The Cytoskeleton • Network of protein filaments throughout cytoplasm • Functions: – Structural framework of cell – Cell/organelle movement • Microfilaments • Intermediate filaments • Microtubules Centrosomes • Contain centrioles: paired cylinders arranged at right angles to one another • Organize microtubules in interphase cells • Organize mitotic spindle during cell division Cilia and Flagella • Hair-like structures important for cellular movement • Cilia – numerous, short, projections extending from cell surface – move materials across surface of cell • Flagella – much longer than cilia – usually move an entire cell Ribosomes • Composed of ribosomal RNA & protein • Sites of protein synthesis • Free ribosomes are loose in cytosol – synthesize proteins found inside the cell • Membrane-bound ribosomes – attached to endoplasmic reticulum or nuclear membrane – synthesize proteins needed for plasma membrane or for export • Inside mitochondria, ribosomes synthesize mitochondrial proteins Ribosomal Subunits • Large + small subunits – made in the nucleolus – assembled in cytoplasm Endoplasmic Reticulum (ER) • Network of membranes that form flattened sacs • Store, package & transport newly synthesized molecules • Detoxification (SER in liver) • Releases Ca+2 ions in muscle contraction (sarcoplasmic reticulum) • Fatty acid & steroid synthesis (liver SER) Endoplasmic Reticulum • Rough ER (RER) – Extension of nuclear membrane – Ribosomes on outer surface – Secretory, membrane & organelle proteins • Smooth ER (SER) – Extension of rough ER – No ribosomes – Detox, FA/steroid synth., Ca release in muscle Golgi Complex • Flattened membranous sacs that process, sort, and deliver proteins & lipids to other parts of cell • Different enzymes allow for modification/packaging of various proteins Lysosomes • Membrane-enclosed vesicles formed from Golgi • Numerous digestive enzymes • Functions – digest foreign substances – autophagy • recycles own organelles – autolysis • tissue damage after death • Tay-Sachs disease – caused by absence of single lysosomal enzyme – glycolipids accumulate & interfere w/ nerve function Peroxisomes • Similar in structure to, but smaller than lysosomes • Contain oxygen-requiring enzymes – Oxidases oxidize various organic compounds – Catalases break down H2O2 • Important in normal catabolism of amino acids and fatty acids • Oxidize toxic substances – Alcohols – Formaldehyde Proteosomes • Destroy unneeded, damaged, or faulty proteins • Proteases cut proteins into small peptides • Faulty proteosomes are possible factor in some degenerative diseases – Fail to break down abnormal proteins – Parkinson’s & Alzheimers Mitochondria • Cellular powerhouses – Site of ATP production • Catabolism of nutrients • O2 required aerobic – Located where O2 enters cell or ATP is used • Bound by double membrane • Cristae – Folds in inner membrane – Enormous surface area for reactions of cellular respiration • Matrix – Central cavity – Site of metabolic reactions NUCLEUS • Directs cellular activity • Controls cell structure • Most body cells have one nucleus (mononucleate) – RBCs are anucleate – Skeletal muscle fibers are multinucleate • Parts of nucleus include – nuclear envelope which is perforated by nuclear pores – nucleolus – genetic material (DNA) • Contains cell’s hereditary units (genes) which are arranged on chromosomes NUCLEUS • 46 (23 pair) human chromosomes – Genes found on chromosomes – Genes direct synthesis of specific protein • Non-dividing cells contain nuclear chromatin – Loosely packed DNA, RNA & protein complex – Histones = proteins that direct DNA folding • Dividing cells contain chromosomes – Tightly packed DNA – DNA copied itself before condensing into chromatids Chromosomes • Each chromosome = long molecule of DNA coiled together with several proteins • Human somatic cells have 46 chromosomes (23 pairs) • Various levels of DNA packing represented by nucleosomes, chromatin fibers, loops, chromatids, & chromosomes PROTEIN SYNTHESIS • Genes expressed as proteins • Proteins determine phys/chem characteristics of cells • DNA is template for protein synthesis • Transcription (txp) – Genetic info in DNA copied onto single-stranded RNA • Three types of RNA – Messenger RNA (mRNA) – Ribosomal RNA (rRNA) – Transfer RNA (tRNA) • Translation – mRNA read by ribosomes – “Message” translated into a. a. sequence of protein Transcription • DNA sense strand = template for creation of mRNA strand • RNA polymerase (RNApol) attaches to promoter sequence & initiates txp • RNApol reaches terminator sequence & detaches txp stops • Genes contain XS information – Pre-mRNA contains introns that are cut out by enzymes – Exons: regions of mRNA code for segments of protein • “gene splicing” • snRNPs – Thus 1 gene can yield several proteins Protein Synthesis • Instructions for making specific proteins found in DNA (your genes) – transcribe that information onto mRNA molecule • each sequence of 3 nucleotides in DNA = base triplet • each triplet transcribed as 3 RNA nucleotides (codon) – translate “message” into sequence of amino acids in order to build protein • each codon must be matched by anticodon found on the tRNA carrying a specific amino acid Translation • Sequence of nucleotides (ntd) on mRNA is “read” by rRNA to construct a protein • Small ribosomal subunit is attachment site for mRNA • Large ribosomal subunit has 2 tRNA binding sites – P site: where tRNA-a.a. attaches to mRNA – A site: holds incoming tRNA-a.a. • Specific tRNA molecules carry specific amino acids • 3-nucleotide sequences = codons – AUG is ALWAYS the start codon – tRNA anticodon = UAC & it codes for methionine • Anticodons on tRNA match specific codons on mRNA so proper a.a can be strung together to create protein Translation Sequence is as follows: • Initiator tRNA • Start codon on mRNA • Functional ribosome formed – initiator tRNA fits into P site on rRNA • Anticodon of tRNA match codons of mRNA • Stop codon on mRNA CELL DIVISION • Process by which cells reproduce themselves – nuclear division (mitosis and meiosis) – cytoplasmic division (cytokinesis) • Somatic cell division: reproduction of any body cell except sex cells – nuclear division (mitosis) – cytokinesis – distribute two sets of chromosomes—one set into each of two separate nuclei • Reproductive cell division: production of gametes – nuclear division (meiosis) – cytokinesis Chromosome Number • Human somatic cells contain 46 chromosomes (23 pairs) • Homologous chromosomes (homologs) = two chromosomes that make up a chromosome pair • A cell with a full set of chromosomes is diploid (2N) • A cell with only one chromosome from each pair is haploid (N) – Mitosis yields diploid cells – Meiosis yields haploid cells Cell Cycle in Somatic Cells • Orderly sequence of events by which cell duplicates its contents and divides in two • Consists of interphase and mitotic phase (Figure 3.28) Interphase • Cell carries on every life process except division • Doubling of DNA and centrosome • Three subphases of interphase: – G1 = replication of cytosolic components (G0 if non-dividing cell) – S = replication of chromosomes • “commitment” stage cell will divide – G2 = cytoplasmic growth Replication of Chromosomes During Interphase • Doubling of genetic material during interphase (S phase) • DNA molecules unzip (histones) • Mirror copy formed along each old strand • Nitrogenous bases pair with complementary base • 2 complete, identical DNA molecules formed Interphase • Cell shows distinct nucleus • DNA present as chromatin • Nuclear membrane in tact MITOSIS: Prophase • Chromatin condenses & shortens into chromosomes – Identical chromatids joined by centromere • Centrosomes migrate to opposite poles • Disintegration of nuclear membrane/nucleolus MITOSIS: Metaphase • Centromeres line up at exact center of mitotic spindle, (metaphase plate or equator) MITOSIS: Anaphase • Splitting & separation of centromeres • Chromatids from each pair move toward opposite poles of cell – appear V-shaped as they are pulled by centromeres • Late anaphase: formation of cleavage furrow begins MITOSIS: Telophase • • • • Begins when chromatid movement stops Chromosomes at opposite poles revert to chromatin form New nuclear envelope/nucleoli form Mitotic spindle breaks up CYTOPLASMIC DIVISION: Cytokinesis • Division of parent cell’s cytoplasm and organelles • Begins late anaphase/ early telophase • Following completion of cytokinesis, interphase begins • Cancer = uncontrolled cell division some anticancer drugs stop this by inhibiting spindle formation Control of Cell Destiny • Three possible destinies of a cell – Live & function without dividing – Growth & division – Death • CDKs crucial for regulation of cell growth/division – Regulated by cyclins • Apoptosis = programmed cell death – Triggered intra- or extracellularly by “cell-suicide” gene – Removes unneeded/unwanted cells • Necrosis = pathological (abnormal) cell death – Stimulates inflammatory response • Tumor-suppressor genes normally inhibit cell division – Ex: p53 arrests cells in G1 damage leads to breast or colon cancers Reproductive Cell Division: Meiosis • Results in production of haploid (n) cells containing only 23 chromosomes • Occurs in two successive stages: – Meiosis I – Meiosis II CELLS AND AGING • Aging = normal, progressive alteration of body’s homeostatic adaptive responses • Physiological signs of aging: – Gradual deterioration in function – Decline in responsiveness – Net decrease in number of cells in body & increased dysfunction of remaining cells • Extracellular components of tissues (e.g., collagen fibers and elastin) also change with age • Theories of aging: – genetically programmed cessation of cell division, glc addition to proteins, free radical rxn, & excessive immune responses DISORDERS: HOMEOSTATIC IMBALANCES • Cancer = group of diseases characterized by uncontrolled cell proliferation • Cells that divide without control develop into a tumor or neoplasm. • Cancerous neoplasm = malignant tumor or malignancy – Capable of metastasizing • spread of cancerous cells to other parts of the body • A benign tumor = noncancerous growth Cancer = Uncontrolled cell division • Hyperplasia = increased number of cell divisions – benign tumor does not metastasize (spread) – malignant tumors spread because detach from tumor & enter blood/lymph • Causes – exposure to carcinogens, x-rays, viruses – every cell has genes that regulate growth & development – mutations in those genes due to radiation or chemical agents causes excess production of growth factors • • Carcinogenesis – multistep process that takes years (and requires many different mutations) to occur Types of Cancer • Carcinomas arise from epithelial cells. • Melanomas = cancerous growths of melanocytes • Sarcomas arise from muscle cells or connective tissues. • Leukemia = cancer of blood-forming organs • Lymphoma = cancer of lymphatic tissue Growth and Spread of Cancer • Cancer cells divide rapidly and continuously. – Trigger angiogenesis • Metastasis occurs when cancer cells leave site of origin & travel to other tissues/organs Causes of Cancer • Normal counterparts of oncogenes = proto-oncogenes – found in every cell – cells fcn normally until a malignant Δ occurs • Anti-oncogenes or tumor-suppressing genes – may produce proteins that normally oppose the action of an oncogene or inhibit cell division • Carcinogenesis = multistep process involving mutation of oncogenes & anti-oncogenes – 10 distinct mutations may have to accumulate in a cell before it becomes cancerous Treatment of Cancer • Difficult because it is not a single disease & because all cells in a tumor do not behave in same way • Various treatments include – Surgery – Chemotherapy – Radiation therapy