3. Plasma Membrane (Cell Membrane) Defines the boundary of the cell and separates intracellular fluids from extracellular fluids Not just a container for the cell, plays a dynamic role in cellular activity Cell membrane, Plasma membrane, Ctyoplasmic membrane, are synonymous

4. Functions Define boundaries of the cell and delineate its compartments Serve as loci of specific functions Facilitate and regulate the movement of substances into and out of the cells and its compartments Contain the receptors for detection of external signals Provide mechanisms for cell to cell communication

5. Singer and Nikolson Fluid mosaic model: 1- mosaic 2- fluid

6. Cell Membrane Phospholipids Phospholipids – modified triglycerides with two fatty acid groups and a phosphate group - main component of cell membranes

7. Singer and Nikolson Fluid mosaic model: 1- mosaic 2- fluid

13. Singer-Nicholson Fluid Mosaic Model Phospholipids are amphipathic - have both hydrophobic and hydrophilic regions – a polar “head” (the phosphate group) and a nonpolar “tail” (the two fatty acids water hydrophilic polar heads Hydrophobic nonpolar tails

14. Fluid Mosaic Model Double layer or bilayer of lipid molecules with imbedded proteins (peripheral and IMPs) referred to as a “unit” membrane. Cell membrane bilayer consists of phospholipids, cholesterol, and glycolipids

15. Fatty acids are essential to membrane structure and function Their long hydrocarbon tails form an effective hydrophobic barrier to the diffusion polar solutes 16 and 18 carbon fatty acids are common Palmitate(16c) stearate(18c) but without double bound Oleate(1double bound) and linoleate (2double bound)

16. Membrane asymmetry Phosphatidylserine, Phosphatidyletanolamine and Phosphatidylinositol are prominent in the inner layer Cholestrol is found in both layers It affects fluidity and permeability

17. Animals exploit the phospholipid asymmetry to distinguish between live and death cells Phosphatidylserine translates to the extracellular monolayer when animal cells undergo apoptosis It signals the neighboring cells, such as macrophages to phgocytose the dead cell

18. Integral membrane proteins are monotopic, single pass or multi pass

19. Membranes contain integral, peripheral and lipid anchored proteins Integral membrane proteins posses one or more hydrophobic regions that exhibit an affinity for hydrophobic interior of the lipid bilayer These molecules cannot be easily removed from membranes Treatment with a detergent that disrupts the lipid bilayer is necessary

20. Membranes contain integral, peripheral and lipid anchored proteins Peripheral membrane proteins lack hydrophobic segments They are bound to membrane surfaces through hydrogen bounding They are more readily removed from membranes than integral proteins by changing pH

21. Fluid Mosaic Model Glycolipids : Cerberosides(neutral glycolipids): each molecules has a single uncharged sugar as its head group Gangliosides : has an oligosacharide head group that contains one or more negatively charged sialic acid residues Gangliosides exposed on the surface of the plasma membrane functions as antigenes recognized by antibodies (blood groups)

23. Sterols are not found in the membranes of prokaryotic cells and are also absent in inner membrane of mitochondria

25. Cholestrol modulates the properties of the lipid bilayers It enhances the permeability- barrier properties of the lipid bilayer It inserts into the bilayer with its hydroxyl group close to polar head groups of phospholipids Its rigid, platelike steroid rings interact with the those regions of the hydrocarbon chains closest to polar head groups

27. Cholesterol and fluidity of membrane Although cholesterol tightens the packing of phospholipids It does not make membranes any less fluid At high concentrations found in most of eucariotic plasma membranes, cholestrol prevents the hydrocarbon chains fro coming together and crystallizing

28. Fluid Mosaic Model – Fluid? Mosaic?

29. The fluidity of lipid bilayer depends on its composition The fluidity of lipid bilayer depends on its composition The fluidity of cell membranes has to be regulated Certain membrane transport processes and enzyme activities, cease when the bilayer viscosity is experimentally increases beyond a threshold level

30. flip flap flip flap Phospholipids molecules very rarely migrate from monolayer on one side on that on the other This process occurs less than once a month Although cholesterol is an exception and can flip flap rapidly

31. Movement in the membranes Movement in the membranes Lipid molecules readily exchange places with their neighbors within a monolayer They are free to move laterally Lipid molecules rotate very rapidly about their long axis They have flexible hydrocarbon chain

33. Mambrane proteins diffuse in the plane of the membrane Membrane proteins do not do flip flap across the lipid bilayer They do rotate about an axis prependicular to the plane of the bilayer (rotational diffusion) Many membrane proteins are able to move laterally within the membrane(lateral diffusion)

34. Functions of Membrane Proteins Transport Enzymatic activity Receptors for signal transduction

35. Functions of Membrane Proteins Intercellular adhesion (CAMs) Cell-cell recognition (Glycocalyx) Attachment to cytoskeleton and extracellular matrix (ECM)

36. Membrane Junctions – Cell to cell “attachments” Glycoproteins in glycocalyx may act as an adhesive Wavy or convoluted margins of adjacent cells fit together in a tongue-and-groove fashion Several types of specific membrane junctions

37. Membrane Junctions – Specific Types Tight Junction (Zonula occludens) – “impermeable” junctions that encircle the cells Desmosome – (Macula adherens) – anchoring junctions along the sides of cells Gap Junction – a nexus or connection that allows chemical substances to pass between cells (connexons)

38. Membrane Junctions – Tight Junctions

39. Tight junctions play a central role in the regulation of permeability in epithelia. A tight junction is composed of strands of integral membrane proteins that seal off the space between adjacent cells. Tight junctions are localized toward the apical face of the cell, the side that faces the fluid or air. The number of tight junction strands determines the tigthness of the epithelium, how leaky it is.

40. The strands of the tight junction proteins also restrict the movement of proteins within the plane of the membrane. Normally, most membrane proteins are free to diffuse within the lipid layer. Tight junction strands block this movement. Proteins that are localized to either the apical and basolateral domains remain in these domains. This molecular segregation enables the cell to establish distinct membrane domains. It establishes an asymmetry to the epithelium and the epithelial cell.

41. Membrane Junctions – Specific Types Tight Junction (zonula occludens) – “impermeable” junctions that encircle some cells Series of Integral Membrane Proteins ( still a bit controversial) that form a fused ring around cells to help prevent molecules from passing between cells “Tight Junction” is a misnomer Common to Epithelial cells (ex. cells lining the digestive tract and the kidney nephron

42. Membrane Junctions - Desmosomes

43. Membrane Junctions – Specific Types Desmosome – (macula adherens) – anchoring junctions along the sides of cells Plaque or thickened area on each cytoplasmic membrane face held together by linker protein filaments (cadherins) Intermediate filaments (tonofilaments) are attached to the plaques and are part of the cytoskeleton

44. Desmosomes are a second type of cadherin-based junction. and build around desmosomal cadherins, known as desmoglein and desmocollin Desmosomes anchor a second cytoskeletal filament network, intermediate filaments, to the plasma membrane Intermediate filaments are strong, elastic polymers. Coupled to the cytoplasmic surface of the desmosome, they form a supracellular network that strengthens tissues, protecting them against mechanical damage.

45. Membrane Junctions – Gap Junctions

46. Membrane Junctions – Specific Types Gap junction – a nexus or connection that allows chemical substances to pass between cells (connexons) Communication channels – ions and small molecules can pass through and move from cell to cell Present in many tissues (ex. liver, cardiac muscle, smooth muscle)

47. Terminology The Cytoplasm is the viscous, semi-fluid (gel-like) matter contained between the cell membrane and the nucleus The aqueous or watery component of the cytoplasm is the Cytosol, which includes ions and soluble macromolecules The insoluble constituents of the cytoplasm include the Organelles and the Cytoskeleton The space outside cells is called the Interstitium. The extracellular fluid is called Interstitial fluid (containing sugars, amino acids, vitamins, hormones, salts, and waste products.

48. Cell Membrane Transport Passive Transport - requires no energy input Diffusion Simple Diffusion Facilitated Diffusion Osmosis Filtration Active Transport - metabolic energy ATP required Primary Active Transport Secondary Active Transport Vesicular Transport Exocytosis Endocytosis

49. Passive Membrane Transport: Diffusion Diffusion is the tendency of molecules or ions to scatter evenly throughout their environment. Molecules are in constant motion (kinetic energy) and move around in a random fashion, colliding with other molecules and/or walls of the container. Molecules move from areas where they are in higher concentration to areas where their concentration is lower Molecules diffuse down their Concentration Gradient

50. Passive Membrane Transport: Diffusion Diffusion is the tendency of molecules or ions to scatter evenly throughout their environment.

51. Passive Membrane Transport: Diffusion Molecules move from areas where they are in higher concentration to areas where their concentration is lower Molecules diffuse down their Concentration Gradient

52. Passive Membrane Transport: Diffusion Molecules diffuse down their Concentration Gradient Gradient – rate of change of some variable ( temperature, pressure, density, concentration) as a function of distance A change in concentration from one place to another High Low No Concentration Gradient

53. Fick’s low J= -DA(∆C/∆X) J: net rate of diffusion in moles or grams per unit time D: diffusion coefficient of the diffusing solute in the membrane A: area of the membrane ∆C: concentration difference across the membrane ∆X: thickness of the membrane

54. Cell Membrane Properties – Semi-Permeable The plasma membrane is a selectively permeable barrier. It only allows “selected” substances to pass through.

55. Passive Membrane Transport: Diffusion The driving force for diffusion is the kinetic energy of the particles The speed or rate of diffusion is influenced by: Molecular size (the smaller, the faster) Temperature (the warmer, the faster) In a closed system, diffusion eventually results in a uniform distribution of particles and the system reaches equilibrium with no net movement

56. Passive Membrane Transport: Simple Diffusion – Simple diffusion – some nonpolar and lipid soluble substances can diffuse directly through the lipid bilayer Ex. Oxygen, carbon dioxide, fat-soluble vitamins

57. Passive Membrane Transport: Facilitated Diffusion – Facilitated Diffusion – some molecules Combine with protein carriers Move through transmembrane protein channels

58. Passive Membrane Transport: Facilitated Diffusion – Facilitated Diffusion – some molecules Combine with protein carriers Move through transmembrane protein channels

60. Cell Membrane Transport Passive Transport - requires no energy input Diffusion Simple Diffusion Facilitated Diffusion Osmosis Filtration Active Transport - metabolic energy (ATP) required Primary Active Transport Secondary Active Transport Vesicular Transport Exocytosis Endocytosis

61. Osmolarity Definition: The total solute concentration of a solution is known as its osmolarity 1 osmol is equal to 1 mol of solute particle 1 Osm = 1 osmol per liter example: 1M glucose  1 Osm 1M NaCl  2 Osm refer to the concentration of the solute particles, also determine the water concentration, higher the osmolarity, lower the water concentration

62. Passive Membrane Transport: Osmosis

63. Osmosis is the net movement (net diffusion) of water across a semipermeable membrane. It is driven by a difference in solute concentrations on the two sides of the membrane. Occurs when the concentration of solvent is different on opposite sides of a membrane (when the concentration of water differs on the two sides of the membrane). Osmolarity- total concentration of solute particles in a solution Semipermeable Selectively Permeable Differentially Permeable

64. Passive Membrane Transport: Osmosis If one side of a membrane has a higher water concentration, chances are that more water molecules will contact that side of the membrane in a given time interval. More contacts mean a greater chance for diffusion and more molecules passing through the membrane. This leads to the net diffusion of water from the side with a higher concentration of water to the side with a lower concentration of water. Different concentrations of solute molecules mean that the concentrations of water molecules are different. Low solute concentration - High water concentration High solute concentration - Low water concentration

65. Effect of Membrane Permeability on Diffusion and Osmosis – Membrane Permeable to Solute and Water

66. Effect of Membrane Permeability on Diffusion and Osmosis – Membrane Permeable to Water Only

67. Osmotic Pressure Osmotic pressure is the pressure that must be applied to a solvent to stop osmosis Pressure

69. Tonicity (tono = Tension) The ability of a solution to change the shape (size) or ‘tone’ of a cell by altering the internal water volume Many molecules, especially intracellular proteins and selected ions cannot diffuse through the cell membrane. A change in their concentration changes the water concentration and can result in the cell having a net loss or gain of water.

70. Tonicity Isotonic – solutions with the same solute concentration as the cytosol (.9% saline or 5% glucose) Hypertonic – solutions having greater solute concentration than the cytosol Hypotonic – solutions having lesser solute concentration than the cytosol

71. Hypotonic – Isotonic - Hypertonic Hypotonic – Isotonic - Hypertonic

72. Passive Membrane Transport: Filtration The passage of water and solutes through a membrane due to hydrostatic pressure Pressure gradient pushes solute-containing fluid from a higher-pressure area to a lower-pressure area Hydrostatic pressure exerted by the blood forces fluid out of the capillaries. Filtration also occurs in the Kidney (glomerulus).

73. Cell Membrane Transport Passive Transport - requires no energy input Diffusion Simple Diffusion Facilitated Diffusion Osmosis Filtration Active Transport - metabolic energy (ATP) required Primary Active Transport Secondary Active Transport Vesicular Transport Exocytosis Endocytosis

74. Active Transport Active Transport - metabolic energy (ATP) required Primary Active Transport Secondary Active Transport Utilize carrier proteins that can bind specifically and reversibly with the transported atoms/molecules Primary Active Transport – energy comes directly from ATP hydrolysis Secondary Active Transport – energy comes from the ionic gradients created by 1° Active Transport Symporter vs. Antiporter

75. solute moves against its concentration gradient primary active transport: ATP directly consumed (e.g., Na+ K+ATPase) secondary active transport: energy of ion gradient (usually Na+) used to move second solute (e.g., nutrient absorption in gut) Active transport

76. Two types of active transporters Primary active transporters use ATP as energy transporter is an ATPase e.g. Na-K ATPase pump, Ca 2+ -ATPase, H + -ATPase, H + /K + ATPase Secondary active transporters use electrochemical gradient

77. Other major primary active-transporters Ca 2+ -ATPase, keep low[Ca 2+ ] i Pump direction: plasma membrane: Cytosol  extracellular organelle membrane: cytosol  organelle H + -ATPase, move H + out of cell to maintain cellular pH H + /K + -ATPase, one H+ out of and one K+ into the cell in the plasma membrane of acid secreting cells in the stomach & kidney

78. Sodium-Potassium Pump (Na + - K + ATPase)

79. Types of Active Transport Secondary active transport – indirect use of an exchange pump (such as the Na + -K + pump) to drive the transport of other solutes

80. Structure of the GLUT family of glucose transporter

82. Na+/glucose co transporter SGLT1: kidney, intestinal. SGLT2: kidney. _ SGLT

83. SGLT1 is in the later part of the proximal tubule a high-affinity/low-capacity cotransporter, that responsible for apical glucose uptake (2:1). SGLT1 carry glucose and galactose and cannot carry fructose. SGLT2 is in the early part of the proximal tubule a high-capacity/low-affinity cotransporter that mediates apical glucose uptake (1:1). SGLT

85. Secondary active transport Co- transport- Na-glucose trasport Counter transpoet- Na- Ca exchanger;3Na-Ca

87. Cell Membrane Transport Passive Transport - requires no energy input Diffusion Simple Diffusion Facilitated Diffusion Osmosis Filtration Active Transport - metabolic energy (ATP) required Primary Active Transport Secondary Active Transport Vesicular Transport Exocytosis Endocytosis

88. Vesicular Transport Transport of large particles, macromolecules, and fluid across plasma and intracellular membranes Exocytosis – out of the cell – moves substance from the cell interior to the extracellular space Endocytosis – into the cell – moves substance from the outside into the intracellular space Phagocytosis – pseudopods engulf solids and bring them into the cell Pinocytosis – fluid-phase endocytosis – cell membrane invaginates (infolds) and brings extracellular fluid and solutes into the cell

89. Endocytosis and Exocytosis endocytosis: plasma membrane fold into the cell, forming small pockets that pinch off to produce intracellular, membrane-bound vesicles that enclosed a small volume of extracellular fluid exocytosis: membrane bound vesicles in the cytoplasm fuse with the plasma membrane and release their contents to the outside of the cell

90. Exocytosis Hormone secretion, neurotransmitter release, mucus secretion, ejection (excretion) of wastes

91. Three types of endocytosis fluid endocytosis (pinocytosis, cell drinking) non-specific, water, ion, nutrients, small molecules phagocytosis (cell eating), eg. Immune system bacteria, large molecules, cell debris internalized phagosomes migrate to and fuse with lysosomes  destroyed

92. Three types of endocytosis receptor mediated endocytosis specific, molecules bind to membrane bound receptors, leads to a concentrated specific ligand in the endocytotic vesicles e.g. cholesterol bind lipoprotein then bind lipoprotein _receptor  endocytosis  cholesterol delivered into the cell_

93. Endocytosis - Phagocytosis Phagocytosis – pseudopods extend, engulf solids, and bring them into the cell (phagosome may fuse with a lysosome → phagolysosome) X bacteria, cell debris

94. Endocytosis - Pinocytosis Pinocytosis – fluid-phase endocytosis – cell membrane invaginates (infolds) and brings extracellular fluid and solutes into the cell

95. Receptor-mediated Endocytosis Receptor-mediated transport – uses Clathrin- coated pits (and also Caveolae) as part of the mechanism for uptake of specific substances (enzymes, Fe, hormones, some viruses)

97. Other Terminology Transcytosis - vesicular transport from one side of the cell to other side Vesicular Trafficking – refers to intracellular traffic – vesicles ‘pinch’ off from organelles and travel to other organelles to deliver their contents

98. Epithelial cells luminal membrane: one surface of an epithelial cellfaces a hollow or fluid filled chamber and the plasmamembrane on this side is referred to basaolateral membrane: the opposite side of luminal membran

99. 2 Pathways for Epithelial Transport diffusion(paracellular pathway) --between adjacent cells --require tight junction --small area available for diffusion transcellular pathway --move into the cell, through cytosol, exit across the whole cell --luminal and basolateral membranes contain different transporters & ion channels