1. Principles of physiologic function Cell membrane physiology NU/Y2 2015

2. Objectives Name different components of cell membrane Describe the role of the cell membrane to maintain cell life Explain the role of protein transporter List the modes of the transport Give examples and apply on a given organ NU/Y2 2015

3. OVERVIEW All cells are enclosed within a membrane that separates the inside of the cell from the outside. This barrier allows the cells to create an internal environment that is optimized to support the biochemical reactions required for normal function. NU/Y2 2015

4. Differences in cell morphology

5. Overview Most cells also contain an identical set of membrane-bound organelles: nuclei, endoplasmic reticulum (ER), lysosomes, Golgi apparatuses, mitochondria. Specialization of cell and organ function is usually achieved by adding a novel organelle or structure, or by altering the mix of membrane proteins that provide pathways for ions and other solutes to move across the barrier. Duong dararith

6. CELLULAR ENVIRONMENT Extracellular fluid (ECF): ions, Glucose, Protein – The biochemical reactions required of cells can only occur if free Ca 2 concentrations are lowered ten-thousand fold Plasma membrane (Cell): Barrier separate ECF from ICF (cytosol) Intracellular fluid (ICF): sustain life – More K, free Protein than EC; slightly more acid NU/Y2 2015

7. Duong dararith

8. Membrane component Membrane component: – Lipid bilayer: barrier function. O 2 CO 2 alcohol (lipophilic) – cholesterol makes it stronger and more rigid – Protein: cell communication and transport hydrophilic molecule Duong Dararith

9. Membrane Structure NU/Y2 2015

10. Membrane Lipid Bilayer Duong Dararith

11. Cholesterol location in the membrane NU/Y2 2015 Physiology Duong Dararith

12. Membrane protein Proteins are grouped on the basis whether they localize to the membrane surface (peripheral) or are integral to the lipid bilayer. Peripheral – IC: enzyme, regulator, skeleton (spectrin, actin, ankrin) – EC: glycophosphatidylinositol (GPI) anchor proteins: enzyme, A/G, adhesion molecule Integral: ion channels transporters receptors

13. Membrane protein NU/Y2 2015 Physiology Duong Dararith

14. Membrane spanning protein NU/Y2 2015 Physiology

15. Diffusion Driven force  movement Gradient concentration is a driven force for simple diffusion ATP is a chemical force  movement against gradient = active transport Fick law – The rate at which molecules such as blue dye cross membranes can be determined using a simplified version of the Fick law: J = P x A (C1-C2)

16. Simple diffusion

17. Diffusion through a lipid bilayer Protein play a role as transporter

18. Charged molecules Electrical force (battery + - electrodes)  movement of charged molecules: (+) dye molecules move to negative (-) electrode. When gradient force = electrical force  electrochemical equilibrium

19. Charge movement induced by an electrical gradient

20. Repellent effect of like charge

21. Pores, channels, carriers Small, nonpolar molecules (e.g., O2 and CO2) diffuse across membranes rapidly, and they require no specialized pathway. Most molecules common to the ICF and ECF are charged, however, meaning that they require assistance from a pore, channel, or carrier protein to pass through the membrane’s lipid core. NU/Y2 2015 Physiology Duong Dararith

22. Transit rate of pore channel carrier NU/Y2 2015 Physiology Duong Dararith

23. Pores Pores are integral membrane proteins containing unregulated, water filled passages that allow ions and other small molecules to cross the membrane. Because AQP is always open, cells must regulate their water permeability by adding or removing AQP from the membrane.

24. Channels Ion channels are trans-membrane proteins that assemble so as to create one or more water-filled passages across the membrane. Channels differ from pores in that the permeability pathways are revealed transiently (channel opening) in response to a membrane- potential change, neurotransmitter binding, or other stimulus, thereby allowing small ions (e.g., Na, K, Ca2, and Cl) to enter and traverse the lipid core. They are selectives for each ion

25. Ion channel opening NU/Y2 2015 Physiology Duong Dararith

26. Carriers Larger solutes, such as sugars and amino acids, are typically assisted across the membrane by carriers. Carriers can be considered enzymes that catalyze movement rather than a biochemical reaction. Translocation involves a binding step, which slows transport rate considerably compared with pores and channels. There are three principal carrier modes: facilitated diffusion, primary active transport, and secondary active transport.

27. Carrier transport for facilitated diffusion Molecule move down its concentration gradient (high to low) via carrier protein transport more efficient than simple diffusion Carrier can be saturated for a finite number  Transport maximum: Tm Ex: GLUT1 or GLUT4 insulin dependent

28. Mode of transport by carrier protein

29. Carrier saturation kinetics

30. NU/Y2 2015 Physiology Duong Dararith

31. Primary active transport = pump Ion move against its concentration gradient Examples – Na-K ATPase Pump – H-K ATPase Pump – Calcium ATPase Pump

32. Na-K ATPase Na-K ATPase: The Na-K ATPase (Na-K exchanger or Na-K pump) is common to all cells and uses the energy of a single ATP molecule to transport three Na out of the cell, while simultaneously bringing two K back from the ECF.

34. Ca 2+ ATPases Ca 2+ ATPases: All cells express a plasma membrane Ca 2+ ATPase (PMCA) that pumps Ca 2+ out of the cytoplasm and is primarily responsible for maintaining intracellular Ca 2+ concentrations at submicromolar levels. A related sarco(endo) plasmic reticulum Ca 2+ ATPase (SERCA) is expressed in the sarcoplasmic reticulum of myocytes and the ER of other cells. SERCA sequesters Ca 2+ in intracellular stores. NU/Y2 2015 Physiology Duong Dararith

37. H-K ATPase H-K ATPase: The H-K ATPase pumps acid and is responsible for lowering stomach pH, for example. It is also found in the kidney, where it is involved in pH balance. Medicine/Physiology

38. H + -K + ATPase Pump

39. Secondary active transport: A second class of active transporters use the energy inherent in the electrochemical gradient of one solute to drive uphill movement of a second solute. Two transport modes: – countertransport and – cotransport.

40. Countertransport:(antiporters) Countertransport: Exchangers (antiporters) use the electrochemical gradient of one solute (e.g., Na + ) to drive flow of a second (e.g., Ca 2+ ) in the opposite direction to the first. Ex: – Na-Ca 2+ exchanger – Na + -H + exchanger and – Cl - -HCO 3 - exchanger

42. Cotransport: (symports) Cotransport: Cotransporters (symports) use the electrochemical gradient of one solute to drive flow of a second or even a third solute in the same direction as the first Ex. – Na-glucose cotransporter – Na–amino acid cotransporter – Na-Cl cotransporter – K-Cl cotransporter – Na-K-2Cl cotransporter

44. Na + -Glucose cotransporter NU/Y2 2015 Physiology Duong Dararith

45. Na + -K + -2Cl - Cotransporter Duong Dararith

46. References Lippincott’s Illustrated Reviews: Physiology. Robin R. Preston 2013 Physiology at a Glance 3 rd edition. Jeremy P.T. Ward 2013 BRS Physiology 5 th edition. Linda S. Costanzo 2011