HISTOLOGY OF CELL MEMBRANE & JUNCTIONS.pptx

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1. CELL MEMBRANE & INTERCELLULAR JUNCTIONS 1

2. Features & Functions of CMs (I) CM is a very dynamic structure It changes shape as the cell alters in shape It participates in transport processes in & out of the cell Keeps constant the intracellular milieu 2

3. Features & Functions of CMs (II) The plasma membrane separates the living cell from its nonliving surroundings Controls traffic into and out of the cell Is selectively permeable , allowing some substances to cross more easily than others 3

4. Features & Functions of CMs (III) Main macromolecules in membranes are lipids and proteins, but include some carbohydrates Most abundant lipids are phospholipids Phospholipids and most other membrane constituents are amphipathic molecules Have both hydrophobic regions and hydrophilic regions 4

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6. Features & Functions of CMs (IV) Distinct internal & external faces Asymmetrical distribution of proteins, lipids, & CHOs is determined as the membrane is being built by ER Molecules that start out on the inside face of the ER end up on outside face of plasma membrane 6

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8. Model of CM Models of membranes were developed long before membranes were first seen with electron microscopes in the 1950s In 1895, Charles Overton hypothesized that membranes are made of lipids because substances that dissolve in lipid enter cells faster than those that are lipid insoluble Twenty years later, chemical analysis confirmed that membranes isolated from red blood cells are composed of lipids and proteins 8

9. Attempts to build artificial membranes provided insight into the structure of real membranes In 1917, Irving Langmuir discovered that phosphilipids dissolved in benzene would form a film on water when the benzene evaporated The hydrophilic heads were immersed in water 9

10. CELL MEMBRANE MODELS (I) Gorter & Grendel (1925), concluded from their study that " chromocytes [red blood cells] are covered by a layer of fatty substances that is two molecules thick” Although not generally thought of as a "model" of cell membranes, Gorter & Grendel did describe a plausible structure for membrane 10

11. Actual membranes adhere more strongly to water than do artificial membranes composed only of phospholipids One suggestion was that proteins on the surface increased adhesion "sandwich" of lipids (arranged in a bilayer) covered on both sides with proteins Later versions of the model included "active patches" & protein-lined pores ( Danielli , 1975) 11

12. CELL MEMBRANE MODELS (III) In 1957 J. D. Robertson proposed a modified version of the membrane model, based primarily on EM, which he called the "unit membrane“ Under TEM, membranes have a characteristic " trilaminar " appearance consisting of 2 darker outer lines & a lighter inner region 2 outer, darker lines are protein layers & inner region the lipid bilayer 12

13. CELL MEMBRANE MODELS (IV) Unit membrane model was eventually replaced in the early 1970s by the current model of the membrane The Fluid mosaic model, was proposed by biochemists S. J. Singer & Garth L. Nicolson (Singer & Nicolson, 1972) Model retains the basic lipid bilayer structure first proposed by Gorter & Grendel & modified by Danielli & Davson & Robertson. Proteins, however, are thought to be globular & to float within the lipid bilayer rather than form the layers of the sandwich-type model 13

14. Fluid Mosaic Model Most acceptable model- Fluid Mozaic The cell membrane is a fluid mosaic of lipids, proteins, & carbohydrates It is responsible for a cell’s communication with & response to its environment 14

15. 15 Phospholids arranged in a bilayer to form a fluid, liquid-crystalline matrix, within which individual lipid molecules can move laterally--- fluidity, flexibility & high resistance & relative impermeability to highly polar molecules

16. Membrane Phospholipids Consist of 2 long hydrophobic hydrocarbon chains linked to a hydrophilic head group These phospholipids, interspersed with cholesterol, are organized as a double layer with the hydrophobic hydrocarbon chains directed towards the centre of the unit membrane and hydrophilic head groups directed outward Lipid composition of each half of the bilayer is asymmetrical 16

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18. Some of the lipids, called glycolipids, have covalently bound oligosaccharide chains which extend outward from the surface of the cell membrane As well as contributing to the structural asymmetry of the lipid bilayer these oligosaccharide chains may also have specific recognition and regulatory roles in the cell's interactions with its environment 18

19. Phospholipids Phospholipids are major components of the cell membrane   They are similar to fats, but have only 2 fatty acids rather than 3 19

20. Membrane molecules are held in place by relatively weak hydrophobic interactions Most of the lipids and some proteins can drift laterally in the plane of the membrane, but rarely flip-flop from one layer to the other Most lipids are randomly mobile in the plane of the membrane 20

21. Cholesterol, wedged bw phospholipid molecules in the plasma membranes of animals, helps stabilize the membrane At relatively warm temperatures, for example (37°C), cholesterol makes the membrane less fluid by restraining the movement of phospholipids 21

22. 22 However, because cholesterol hinders the close packing of phospholipids, it also lowers the temperature required for the membrane to solidify, thereby helping to maintain fluidity

23. 23 Proteins Proteins are the most structurally sophisticated molecules known, & account for more than 50% of the dry weight of most cells Although they are diverse, humans have tens of thousands of different proteins, each with a specific structure and function

24. Membrane Proteins The nature of these membrane proteins was studied by Unwin & Henderson (1984) They found that the portion of the protein that spans the lipid bilayer is hydrophobic in nature ( i.e. , similar to the lipids forming the bilayer) & arranged in a 3D shape, often in the form of an alpha helix 24

25. Proteins are a major component of membranes. These proteins can be divided into 2 groups, integral proteins & peripheral proteins Peripheral proteins are only loosely bound to the surface of the lipid bilayer of the cell membrane 25

26. Peripheral proteins are not embedded in the lipid bilayer They are loosely bound to the surface of the membrane, often to the exposed parts of integral proteins 26

27. Integral proteins are firmly embedded within the lipid bilayer Some are embedded in either the inner or the outer part of the lipid bilayer but other proteins completely span the lipid bilayer These latter proteins are known as transmembrane proteins 27

28. 28 Hydrophobic regions completely span the hydrophobic interior of the membrane Hydrophilic ends of the molecule are exposed to the aqueous solutions on either side of the membrane Transmembrane Proteins

29. 29 Proteins are much larger than lipids & move more slowly, but some do drift Some membrane proteins seem to move in a highly directed manner, however, many others seem to be held virtually immobile by their attachment to the cytoskeleton

30. 30 Carbohydrates Membrane carbohydrates are usually branched oligosaccharides with fewer than 15 sugar units. Some of these oligosaccharides are covalently bonded to lipids-glycolipids Most are covalently bonded to proteins- glycoproteins

31. The oligosaccharides on the external side of the plasma membrane vary from species to species, among individuals of the same species, & even from one cell type to another in a single individual 31

32. The diversity of the molecules & their location on the cell's surface enable oligosaccharides to function as markers that distinguish one cell from another 32

33. It is rare, however, for a molecule to flip-flop transversely across the membrane, switching from one phospholipid layer to the other; to do so, the hydrophilic part of the molecule would have to cross the hydrophobic core of the membrane 33

34. Membranes are not static sheets of molecules locked rigidly in place A membrane is held together primarily by hydrophobic interactions, which are much weaker than covalent bonds Most lipids are randomly mobile in the plane of the membrane with an average migration rate of 22 µm/sec 34

35. Temperature affects the fluidity of the membrane . A membrane remains fluid as temperature decreases, until finally, at some critical temperature, the membrane solidifies The temperature at which a membrane solidifies depends on its fatty acid composition 35

36. A membrane rich in phospholipids with unsaturated hydrocarbon tails will remain fluid to a lower temperature because the kinks where the double bonds are located prevent the hydrocarbons from packing as closely together as saturated hydrocarbons 36

37. However, a cell can alter the lipid composition of its membranes to some extent as an adjustment to changing temperature For instance, in many plants that tolerate extreme cold, such as winter wheat, the % of unsaturated phospholipids increases in autumn, an adaptation that keeps the membranes from solidifying during winter. 37

38. Intercellular Junctions 38

39. Intercellular junctions Zonula Occludens Zonula Adherens Gap Junctions Desmosomes Hemidesmosomes 39

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41. Tight Junctions ( Zonulae Occludens )   Transmembrane proteins called  claudins  join the plasma membranes of two cells to create a barrier that limits diffusion of ions and solutes between the cells and molecules between apical and basolateral domains of the plasma membrane. Specialized "belts" that bind 2 cells tightly to each other; prevent materials from flowing bw cells in either direction Interlocking membrane proteins Found near surface of cells. Most apical of junctions 41

42. Tight Junctions ( Zonulae Occludens ) connect heart and smooth muscle cells, but not skeletal muscle cells. allow epithelia to separate the interior of the body from the external environment define the boundary between the biochemically distinct apical and basolateral domains of the plasma membrane of polarized epithelial cells Claudins are the main structural proteins of tight junction 42

43. Tight Junctions ( Zonulae Occludens ) Extremely tight juctions : found where epithelia must maintain high ion gradients, eg ., the distal tubules of the kidney, where urine is concentrated. Leaky tight junctions: found where ion gradients across epithelia are small but a barrier is required for large solutes, proteins, and leukocytes ( eg , in most blood vessels) 43

44. Zona Adherens/ Adherens Junctions the first connections established within developing sheets of epithelial cells Use transmembrane proteins called  cadherins   Link neighboring cells and connect to actin filaments in the cytoplasm. 44

45. Zona Adherens/ Adherens Junctions use homophilic interactions of E- cadherins to bind epithelial cells to their neighbors. are essential for viability from the earliest stages of embryonic development. In mature epithelia, a belt-like adherens junction, called the zonula adherens , encircles 45

46. Zona Adherens/ Adherens Junctions anchor muscle cells to the extracellular matrix. can transmit mechanical forces between cells and reinforce tissues, because the cytoplasmic domains of the E- cadherins are linked to the actin cytoskeleton 46

47. 47 Desmosomes/Macula Adherens Desmosomes:  Another type of cadherin links cells together and connects to cytoplasmic intermediate filaments. Has an identical disc-shaped structure at the cytoplasmic surface of each adjacent cell Found in superficial layers of skin © Abraham A.A. Osinubi (2010)

48. Desmosomes/Macula Adherens CM in this region are very straight & are further apart (>30 nm)than the usual 20 nm Belt, button & hemidesmosomes 48

49. Desmosome (macula adherens ) Can be sited anywhere on the cell surface Intercellular gap is about 25nm, filled with electron-dense filamentous material running transversely across it and also marked by a series of densely staining bands running parallel to the cell surfaces. Within the cells on either side there is a dense under-coating of the plasma membrane, into which the ends of intermediate filaments are inserted. Filaments extremely numerous and large in stratum spinosum of epidermis, where strong cohesion is needed. 49

50. Desmosome (macula adherens ) The development of animal tissues depends on desmosomes. Loss-of-function mutations can lead to mechanical failures. Eg ., mutations in the plakoglobin gene can be lethal in mice and humans during embryogenesis, owing to disruption of the heart. Similarly, mutations in the desmoplakin gene cause skin and cardiac defects that can be fatal. Loss of desmosomes is associated with the spread of epithelial cancer cells because d esmosomal proteins participate in signal transduction in regulation mitosis. 50

51. Desmosome (macula adherens ) Desmosomes use cadherins to provide strong adhesions reinforced by intermediate filaments between epithelial and muscle cells. In epithelia, these junctions are small, disk-shaped, “spot welds” between adjacent cells. Desmosomes in the heart are more complicated because they are mixed with adherens junctions Desmosomal cadherins connect to cytoplasmic intermediate filaments via adapter proteins 51

52. 52 Gap Junctions (I) Transmembrane proteins called con­nexins form channels for small molecules to move between the cytoplasms of neighboring cells. Can occur almost anywhere along the lateral membranes of most epithelial cells; formed by 2 connecting protein rings embedded in cell membrane of adjacent cells Allows passage of water, small solutes, but not macromolecules (proteins, nucleic acids)

53. Gap Junctions (II) channel proteins ( connexons ) interlock and form pores abundant in cardiac and smooth muscle 53

54. Gap Junctions in Disease Point mutations in connexin genes cause remarkably specific defects in humans. Recessive mutations in the connexin-26 gene are the most common causes of inherited human deafness. As many as 1 in 30 people are carriers, and their mutations may contribute to hearing loss late in life. Connexin-26 participates in the transport of K+ in the epithelia supporting the sensory hair cells in the ear. 54

55. Gap Junctions in Disease Patients with one of more than 100 different mutations in the connexin-32 gene can suffer from degeneration of the myelin sheath around axons, an X-linked variant of Charcot-Marie-Tooth disease. Many human tissues express connexin-32, but the pathology is confined to myelin. 55

56. Gap Junctions in Disease The stability of myelin might depend on intracellular gap junctions between layers of the myelin sheath that provide a pathway between the metabolically active cell body and the deep layers of the sheath near the axon. Defects in myelin membrane proteins cause other forms of Charcot-Marie-Tooth disease. 56

57. Hemidesmosomes Adhesion to the extracellular matrix is fundamentally different from intercellular adhesion because integrins , (and NOT homophilic interactions of cadherins ), provide the transmembrane link between the cytoskeleton and ligands in the extracellular matrix Hemidesmosomes are morphologically similar to demosomes but differ remarkably are molecular level Like desmosomes, hemidesmosomes have a dense plaque on the cytoplasmic surface of the plasma membrane that anchors loops of intermediate filaments. 57

58. Hemidesmosomes  Integrins  connect cytoplasmic intermediate filaments to the basal lamina across the plasma membrane. Anchoring junctions between the bases of epidermal cells and extracellular structures of the underlying connective tissue. On the cytoplasmic side of the membrane there is a dense coat into which keratin filaments are inserted. Use integrins as their adhesion molecules rather than cadherins . 58

59. The hemidesmosomes of simple epithelia use α6β4 integrin to adhere to laminin-5 in the basal lamina. More complex hemidesmosomes of stratified epithelial cells have, in addition to α6β4-integrin, a second transmembrane adhesion protein, type XVII collagen which forms triple helix that anchor membrane to the basal lamina. Mutations in the genes for any of the hemidesmosome proteins cause blistering skin diseases known as epidermolysis bullosa. Can affect other tissues that depend on hemidesmosomes, including the cornea, gastrointestinal tract, and muscles. Hemidesmosomes 59

60. Focal adhesions 60 Integrins associated with cytoplasmic actin filaments adhere to the extracellular matrix.