1. Human Physiology 人体生理学 Qiang XIA ( 夏强 ), MD & PhD Department of Physiology Room C518, Block C, Research Building, School of Medicine Tel: 88208252 Email: xiaqiang@zju.edu.cn

2. MOVEMENT OF MOLECULES ACROSS CELL MEMBRANES 物质的跨膜转运

3. Outline  Cell structure  Simple diffusion  Facilitated diffusion  Active transport  Endocytosis and exocytosis

4. Sizes, on a log scale

5. Ostrich egg

6. Electron Micrograph of organelles in a hepatocyte (liver cell)

7. Organelles have their own membranes

8. Cell Membrane (plasma membrane) 细胞膜

9. Electron micrograph and sketch of plasma membrane surrounding a human red blood cell

10. Phospholipid bilayer

11. Circles represent amino acids in the linear sequence of the protein Schematic cartoon of a transmembrane protein The amino acids along the membrane section are likely to have non-polar side chains

12. Structure of cell membrane: Fluid Mosaic Model ( Singer & Nicholson, 1972 )

13. Drawing of the fluid-mosaic model of membranes, showing the phospholipid bilayer and imbedded proteins

14. Composition of cell membrane:  Lipids 脂类  Proteins 蛋白质  Carbohydrates 糖类

15. Lipid Bilayer Phospholipid Phosphatidylcholine Phosphatidylserine Phosphatidylethanolamine Phosphatidylinositol Cholesterol Sphingolipid

17. Lipid mobility enhancing membrane fluidityreducing membrane fluidity Rotation

18. Membrane proteins Integral (intrinsic) proteins Peripheral (extrinsic) proteins Integral protein Peripheral protein

19. Integral proteins

20. Functions of membrane proteins Adhesion Some glycoproteins attach to the cytoskeleton and extracellular matrix.

21. Carbohydrates GlycoproteinGlycolipid

22. Membrane Transport 跨膜转运 Lipid Bilayer -- primary barrier, selectively permeable

23.  Simple Diffusion  Facilitated Diffusion  Active Transport  Endocytosis and Exocytosis Primary Active Transport Secondary Active Transport Membrane Transport

24. Over time, solute molecules placed in a solvent will evenly distribute themselves. START: Initially higher concentration of molecules randomly move toward lower concentration. Diffusional equilibrium is the result (Part b).

25. At time B, some glucose has crossed into side 2 as some cross into side 1.

26. Note: the partition between the two compartments is a membrane that allows this solute to move through it. Net flux accounts for solute movements in both directions.

27. Simple Diffusion 单纯扩散 Relative to the concentration gradient movement is DOWN the concentration gradient ONLY (higher concentration to lower concentration) Rate of diffusion depends on The concentration gradient Charge on the molecule Size Lipid solubility Temperature

28. Facilitated Diffusion 易化扩散  Carrier-mediated diffusion 载体中介的扩散  Channel-mediated diffusion 通道中介的扩散

29. The solute acts as a ligand that binds to the transporter protein…. A cartoon model of carrier-mediated diffusion … and then a subsequent shape change in the protein releases the solute on the other side of the membrane.

30. In simple diffusion, flux rate is limited only by the concentration gradient. In carrier- mediated transport, the number of available carriers places an upper limit on the flux rate.

31. Characteristics of carrier-mediated diffusion: net movement always depends on the concentration gradient  Specificity  Saturation  Competition

32. –Channel-mediated diffusion 3 cartoon models of integral membrane proteins that function as ion channels; the regulated opening and closing of these channels is the basis of how neurons function.

33. A thin shell of positive (outside) and negative (inside) charge provides the electrical gradient that drives ion movement across the membranes of excitable cells.

34. The opening and closing of ion channels results from conformational changes in integral proteins. Discovering the factors that cause these changes is key to understanding excitable cells.

35. Characteristics of ion channels  Specificity  Gating

36. Channel Types:  Voltage-gated Channel  Ligand-gated Channel  Stretch-sensitive Channel  Others

37. Outside Inside NH 2 CO 2 H IIIIIIIV ++++++ ++++++ ++++++ ++++++ Voltage-gated Channel –e.g. Voltage-dependent Na + channel

38. Na + channel

39. Balloonfish or fugu

40. Closed Activated Inactivated Na + channel conformation –Open-state –Closed-state

41. Ligand-gated Channel –e.g. N 2 -ACh receptor channel

42. Stretch-sensitive Channel Closed Open Stretch

43. Aquaporin  Aquaporins are water channels that exclude ions  Aquaporins are found in essentially all organisms, and have major biological and medical importance

44. The Nobel Prize in Chemistry 2003 "for discoveries concerning channels in cell membranes" Peter AgreRoderick MacKinnon "for the discovery of water channels" "for structural and mechanistic studies of ion channels" http://nobelprize.org/nobel_prizes/chemistry/laureates/2003/public.html

45. The dividing wall between the cell and the outside world – including other cells – is far from being an impervious shell. On the contrary, it is perforated by various channels. Many of these are specially adapted to one specific ion or molecule and do not permit any other type to pass. Here to the left we see a water channel and to the right an ion channel.

46. Peter Agre’s experiment with cells containing or lacking aquaporin. The aquaporin is necessary for making the cell absorb water and swell

47. Passage of water molecules through the aquaporin AQP1. Because of the positive charge at the center of the channel, positively charged ions such as H3O+, are deflected. This prevents proton leakage through the channel.

48. Model for water permeation through aquaporin

49. In both simple and facilitated diffusion, solutes move in the direction predicted by the concentration gradient. In active transport, solutes move opposite to the direction predicted by the concentration gradient. membrane

50. Active transport 主动转运  Primary active transport 原发性主动转运  Secondary active transport 继发性主动转运

51. Primary Active Transport making direct use of energy derived from ATP to transport the ions across the cell membrane

52. The transported solute binds to the protein as it is phosphorylated (ATP expense).

53. Concentration gradient of Na + and K + Extracelluar (mmol/L) Intracellular (mmol/L) Na + 140.015.0 K + 4.0150.0

54. Here, in the operation of the Na + -K + -ATPase, also known as the “sodium pump,” each ATP hydrolysis moves three sodium ions out of, and two potassium ions into, the cell.

55. electrogenic pump Na + -K + pump (Na + pump, Na + -K + ATPase)

56. Physiological role of Na + -K + pump –Maintaining the Na + and K + gradients across the cell membrane –Partly responsible for establishing a negative electrical potential inside the cell –Controlling cell volume –Providing energy for secondary active transport

57. Other primary active transport  Primary active transport of calcium  Primary active transport of hydrogen ions  etc.

58. Secondary Active Transport The ion gradients established by primary active transport permits the transport of other substances against their concentration gradients

59. Secondary active transport uses the energy in an ion gradient to move a second solute.

60. Cotransport the ion and the second solute cross the membrane in the same direction (e.g. Na + -glucose, Na + -amino acid cotransport) Countertransport the ion and the second solute move in opposite directions (e.g. Na + -Ca 2+, Na + -H + exchange)

63. Endocytosis and Exocytosis 入胞与出胞

64. Alternative functions of endocytosis: 1.Transcellular transport 2.Endosomal processing 3.Recycling the membrane 4.Destroying engulfed materials

65. Endocytosis

66. Exocytosis

67. Two pathways of exocytosis Constitutive exocytosis pathway -- Many soluble proteins are continually secreted from the cell by the constitutive secretory pathway Regulated exocytosis pathway -- Selected proteins in the trans Golgi network are diverted into secretory vesicles, where the proteins are concentrated and stored until an extracellular signal stimulates their secretion

68. Epithelial Transport

71. Glands

72. Summary Diffusion: solute moves down its concentration gradient: simple diffusion: small (e.g., oxygen, carbon dioxide) lipid soluble (e.g., steroids) facilitated diffusion: requires transporter (e.g., glucose)

73. Active transport: 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) Exo- and endo- cytosis: large scale movements of molecules

74. Thank you for your attention!