Human Physiology

人体生理学

Qiang XIA (夏强 ), MD & PhDDepartment of PhysiologyRoom C518, Block C, Research Building, School of MedicineTel: 88208252Email: xiaqiang@zju.edu.cn

Course Structure

Lectures: 80 academic hours5 a.h./week2 a.h. on Tue., 3 a.h. on Fri.

Practicals: 64 a.h.4 a.h./week

Evaluation

Participation in practicals: 5%Practical reports: 15%Weekly assessments & midterm exam: 30%Final examination: 50%

Recommended textbook

Widmaier EP, Raff H, Strang KT (2006) Vander’s Human Physiology: The Mechanisms of Body Function, Tenth Edition. McGraw-Hill.

Course website

Medical School Course Center: http://10.71.121.158

Course website:http://10.71.121.158/G2S/Template/View.aspx?act

ion=view&courseType=0&courseId=27123

MOVEMENT OF MOLECULES ACROSS CELL MEMBRANES

物质的跨膜转运

Outline

Cell structureSimple diffusionFacilitated diffusionActive transportEndocytosis and exocytosis

Sizes, on a log scale

Ostrich egg

Electron Micrograph of organelles in a hepatocyte (liver cell)

Organelles have their own membranes

Cell Membrane (plasma membrane)细胞膜

Electron micrograph and sketch of plasma membranesurrounding a human red blood cell

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Schematic cartoon of a transmembrane protein

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Structure of cell membrane:

Fluid Mosaic Model (Singer & Nicholson, 1972)

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

Composition of cell membrane:

Lipids 脂类

Proteins 蛋白质

Carbohydrates 糖类

Lipid Bilayer

Phospholipid

Phosphatidylcholine

Phosphatidylserine

Phosphatidylethanolamine

Phosphatidylinositol

Cholesterol

Sphingolipid

Lipid mobility

enhancing membrane fluidityreducing membrane fluidity

Rotation

Membrane proteinsIntegral (intrinsic) proteins

Peripheral (extrinsic) proteins

Integral protein Peripheral

protein

Integral proteins

Functions of

membrane

proteins

Adhesion Some glycoproteins attach to the cytoskeleton and extracellular matrix.

CarbohydratesGlycoprotein Glycolipid

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

Simple Diffusion

Facilitated Diffusion

Active Transport

Endocytosis and Exocytosis

Primary Active TransportPrimary Active TransportSecondary Active TransportSecondary Active Transport

Membrane Transport

Over time, solute moleculesplaced in a solventwill evenly distribute themselves.

START: Initially higher concentration of molecules randomly

move toward lower concentration.

Diffusional equilibrium is the result (Part b).

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

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.

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

Facilitated Diffusion 易化扩散

Carrier-mediated diffusion Carrier-mediated diffusion 载体中介的扩散载体中介的扩散

Channel-mediated diffusion Channel-mediated diffusion 通道中介的通道中介的

扩散扩散

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.

In simple diffusion,flux rate is limited only by the concentration gradient.

In carrier-mediated transport, the number of available carriersplaces an upper limit on the flux rate.

Characteristics of carrier-mediated diffusion:

net movement always depends on the

concentration gradient  

Specificity

Saturation

Competition

– Channel-mediated diffusionChannel-mediated diffusion

3 cartoon models of integral membraneproteins that functionas ion channels; theregulated opening and closing of these channels is the basis of howneurons function.

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

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.

Characteristics of ion

channels

Specificity

Gating

Channel Types:

Voltage-gated Channel

Ligand-gated Channel

Stretch-sensitive Channel

Others

Outside

Inside

NH2CO2H

I II III IV

+++

+++

+++

+++

Voltage-gated ChannelVoltage-gated Channel

– e.g. Voltage-dependent Nae.g. Voltage-dependent Na++ channelchannel

NaNa++ channel channel

NaNa++ channel channel

Balloonfish or fugu

Closed Closed Activated Activated InactivatedInactivated

NaNa++ channel conformation channel conformation– Open-stateOpen-state

– Closed-stateClosed-state

Ligand-gated Channel Ligand-gated Channel

– e.g. Ne.g. N22-ACh receptor channel-ACh receptor channel

Stretch-sensitive ChannelStretch-sensitive Channel

Closed OpenClosed Open

Stretch

Aquaporin

Aquaporins are water channels that exclude ions

Aquaporins are found in essentially all organisms, and have major biological and medical importance

The Nobel Prize in Chemistry 2003

"for discoveries concerning channels in cell membranes"

Peter Agre Roderick 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

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.

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

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.

Model for water permeation through aquaporin

In both simple and facilitated diffusion, solutes move in the direction predicted by the concentration gradient.

In active transport, solutes move opposite to thedirection predicted by the concentration gradient.

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Which of the following would decrease the rate of diffusion?a. increasing the size of the diffusing solute

b. increasing the temperature

c. increasing the concentration gradient

d. increasing the surface area for diffusion

e. All of the choices would increase the rate of diffusion

QUIZ

Which of the following would decrease the rate of diffusion?a. increasing the size of the diffusing solute

b. increasing the temperature

c. increasing the concentration gradient

d. increasing the surface area for diffusion

e. All of the choices would increase the rate of diffusion

QUIZ

Carrier- mediated transport

a. involves a specific membrane protein that functions as a carrier molecule.

b. always involves the movement of substances against a concentration gradient.

c. always requires the direct expenditure of energy.

d. Both involves a specific membrane protein that functions as a carrier molecule and always involves the movement of substances against a concentration gradient are correct.

e. All of the choices are correct.

QUIZ

Carrier- mediated transport

a. involves a specific membrane protein that functions as a carrier molecule.

b. always involves the movement of substances against a concentration gradient.

c. always requires the direct expenditure of energy.

d. Both involves a specific membrane protein that functions as a carrier molecule and always involves the movement of substances against a concentration gradient are correct.

e. All of the choices are correct.

QUIZ

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

Primary Active Transport

making direct use of energy derived from making direct use of energy derived from

ATP to transport the ions across the cell ATP to transport the ions across the cell

membranemembrane

The transported solute binds to the proteinas it is phosphorylated (ATP expense).

Concentration gradient of Na+ and K+

Extracelluar (mmol/L) Intracellular (mmol/L)

Na+ 140.0 15.0

K+ 4.0 150.0

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.

electrogenic pump

NaNa++-K-K++ pump (Na pump (Na++ pump, Na pump, Na++-K-K++ ATPase)ATPase)

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

Other primary active transport

Primary active transport of calciumPrimary active transport of hydrogen ionsetc.

Secondary Active Transport

The ion gradients established by primary active The ion gradients established by primary active

transport permits the transport of other transport permits the transport of other

substances against their concentration gradientssubstances against their concentration gradients

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

Cotransportthe ion and the second solute cross the

membrane in the same direction(e.g. Na+-glucose, Na+-amino acid

cotransport)

Countertransportthe ion and the second solute move in opposite directions(e.g. Na+-Ca2+, Na+-H+ exchange)

Which of the following statements about the Na,K pump is false?

a. It transports Na+ out of cells and K+ into cells.

b. It binds to and hydrolyzes ATP.

c. It is constantly active in all cells.

d. Its activity requires the expenditure of metabolic energy.

e. It transports Na+ and K+ in a 1:1 ratio.

QUIZ

Which of the following statements about the Na,K pump is false?

a. It transports Na+ out of cells and K+ into cells.

b. It binds to and hydrolyzes ATP.

c. It is constantly active in all cells.

d. Its activity requires the expenditure of metabolic energy.

e. It transports Na+ and K+ in a 1:1 ratio.

QUIZ

If the ATP-generating mechanisms in a cell are poisoned and the cell has depleted its ATP reserves,

a. primary active transport of molecules would cease immediately.

b. secondary active transport of molecules would cease immediately.

c. eventually there will be no potential difference across the membrane.

d. primary active transport of molecules would cease immediately and secondary active transport of molecules would cease immediately are correct.

e. primary active transport of molecules would cease immediately and eventually there will be no potential difference across the membrane are correct.

QUIZ

If the ATP-generating mechanisms in a cell are poisoned and the cell has depleted its ATP reserves,

a. primary active transport of molecules would cease immediately.

b. secondary active transport of molecules would cease immediately.

c. eventually there will be no potential difference across the membrane.

d. primary active transport of molecules would cease immediately and secondary active transport of molecules would cease immediately are correct.

e. primary active transport of molecules would cease immediately and eventually there will be no potential difference across the membrane are correct.

QUIZ

Endocytosis and Exocytosis 入胞与出胞

Alternative functions of endocytosis:

1. Transcellular transport

2. Endosomal processing

3. Recycling the membrane

4. Destroying engulfed materials

Endocytosis

Exocytosis

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

Epithelial Transport

Glands

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)

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 movesecond solute (e.g., nutrient absorption in gut)

Exo- and endo- cytosis:

large scale movements of molecules

Thank you for your attention!