Ch 5: Membrane DynamicsCh 5: Membrane Dynamics

Cell membrane structures and functions– Mass balance and homeostasis– Diffusion– Protein-mediated transport– Vesicular transport– Transepithelial transport– Osmosis and tonicity– (The resting membrane potential)

Mass Balance• Law of mass balance applies to human body• 2 options for output:– Excretion– Metabolism (production of metabolites)

• Liver is major organ for clearance• Other ways to clear molecules: Kidneys, saliva,

sweat, breast milk, hair, lungs

Fig 5-2

Homeostasis• Body’s ability to maintain relatively stable

internal environment (dynamic steady state!)

• H2O is in osmotic equilibrium (free movement)

• Yet: selective permeability of cell membrane leads to chemical and electrical disequilibrium between ECF and ICF

• Whole body is electrically neutral

Transport Across Cell MembraneCell membrane is selectively permeable

Permeability is variable

Relevant properties of membrane- Availability of transport proteins- Cholesterol content

Relevant properties of molecule - Size and - Charge (lipid solubility)

Passive vs. active transport

Properties of DiffusionProperties of DiffusionPassive – based on inherent Ekin of all molecules

In open system or across partitions

Net movement down chemical / conc. gradient until state of equilibrium reached

Direct correlation to temperature (why?)

Indirect correlation to molecule size

Slower with increasing distance

Distance – Time RelationshipTime for diffusion to progress to given distance ~ to

distance squared

diffusion over 100 m takes 5 sec.

diffusion over 200 m takes ??

diffusion over 400 m takes ??

diffusion over 800 m takes ??

Diffusion effective only over short distances!

Simple DiffusionSimple Diffusion

• Movement of lipophilic molecules directly through phospholipid bilayer. E.g.?

• Diffusion rate

• Diffusion rate to membrane surface area

1

Thickness of membrane

Fick’s law of Diffusion

surface x conc. X membrane area gradient permeability

membrane thickness

Diffusionrate

Fig 5-6

Protein Mediated TransportFor all lipophobic moleculesTwo mediated transport categories:

1. Passive transport (facilitated diffusion)2. Active transport

Two categories of transporter proteins1. Channel proteins (rapid but not very selective – for

small molecules only)2. Carrier proteins (slower but very selective – also for

large molecules)

Three other functions of membrane proteins

Fig 5-7

Channel ProteinsChannel Proteins• For small molecules e.g.?

• Aquaporins

• > 100 ion channels

• Selectivity based on diameter and ________________

• All have “gate” regionFig 5-10

Open Channels vs. Open Channels vs. Gated ChannelsGated Channels

= pores

Have gates, but gates are open most of the time.

Also referred to as “leak channels”.

Gates closed most of the time

Chemically gated channels (controlled by messenger molecule or ligand)

Voltage gated channels (controlled by electrical state of cell)

Mechanically gated channels (controlled by physical state of cell: temp.; stretching of cell membrane etc.)

Carrier Proteins Carrier Proteins (2(2ndnd type of transport protein) type of transport protein)

• Never form direct connection between ECF and ICF

• Bind molecules and change conformation

• Used for small organic molecules (such as?)

• Ions may use channels or carriers

• Rel. slow (1,000 to 1 Mio / sec)

Compare to Fig 5-13

Uniport vs.Uniport vs. Cotransport CotransportSymport Molecules are

carried in same direction

Examples: Glucose and Na+

Antiport Molecules are

carried in opposite direction

Examples: Na+/K+ pump

Facilitated DiffusionFacilitated DiffusionForm of carrier mediated, passive transportSome characteristics same as simple

diffusion

but also:• specificity• competition• saturation

More later Fig 5-14

Summary: Passive TransportSummary: Passive Transport

= Diffusion (Def?) – 3 types:

1. Simple diffusion

2. Osmosis

3. Facilitated diffusion (= mediated transport)

Active TransportActive Transport• Movement from low to high conc.• ATP needed• Creates state of ____ equilibrium • Primary (direct) active transport

– ATPases or “pumps” (uniport and antiport)– examples?

• Secondary (indirect) active transport – Symport or antiport

11oo Active Transport Active Transport • ATP energy directly fuels transport

• Most important example: Na+/K+ pump = sodium-potassium ATPase (uses up to 30% of cell’s ATP)

• Establishes Na+ conc. gradient

Epot. can be harnessed for other cell functions

ECF: high [Na+], low [K+]

ICF: high [K+], low [Na+]

Fig 5-17 Fig 5-16

Secondary Active Transport Secondary Active Transport • Indirect ATP use: uses Epot. stored in conc.

gradient • Coupling of Ekin of one molecule with

movement of another molecule• Example: Na+ / Glucose symporter

other examples• 2 mechanisms for Glucose transport

Fig 5-18

Specificity, Competition, and Saturation characterize Carrier-Mediated

Transport

• Specificity (e.g.: GLUT transporters for hexoses)

• Competition (competitive inhibition applied in medicine, e.g.: gout)

• Saturation (numbers of carriers can be adjusted)

Vesicular TransportVesicular TransportMovement of large molecules across

cell membrane:1. Phagocytosis2. Endocytosis

– Pinocytosis– Receptor mediated endocytosis– Potocytosis

3. Exocytosis

PhagocytosisPhagocytosis• Requires energy

• Cell engulfs particle into vesicle via pseudopodia formation

• E.g.: some WBCs engulf bacteria

• Vesicles formed are much larger than those formed by endocytosis

• Phagosome fuses with lysosomes ? (see Fig. 5-23)

EndocytosisEndocytosis• Requires energy • No pseudopodia - Membrane surface indents• Smaller vesicles• Nonselective: Pinocytosis for fluids & dissolved

substances• Selective:

– Receptor Mediated Endocytosis via clathrin-coated pits - Example: LDL cholesterol and Familial Hypercholesterolemia

– Potocytosis via caveolae Fig 5-24

ExocytosisExocytosisIntracellular vesicle fuses with membrane Requires energy and Ca2+

Examples: goblet cells, fibroblasts; receptor insertion; waste removal

Movement through Epithelia: Movement through Epithelia: Transepithelial Transport

Uses combination of active and passive transport

Molecule must cross two phospholipid bilayers

Polarity of epithelial cells → Apical and basolateral cell membrane has different proteins:Na+- glucose transporter on apical membraneNa+/K+-ATPase only on basolateral membrane

Fig 5-26

Transcytosis• Endocytosis vesicular transport exocytosis • Moves large proteins intact

• Examples: – Absorption of maternal antibodies from

breast milk

– Movement of proteins across capillary endothelium

OsmosisMovement of water down its concentration

gradient.

Osmotic pressure

Opposes movement of water across membrane

Water moves freely in body until osmotic equilibrium is reached

Compare to Fig. 5-29

Molarity vs. Osmolarity

In chemistry:• Mole / L• Avogadro’s # / L

In PhysiologyImportant is not # of

molecules / L but# of particles / L:

osmol/L or OsM

Why?

Osmolarity takes into account the dissociation of molecules in solution

Convert Molarity to OsmolarityOsmolarity = # of particles / L of solution

• 1 M glucose = ? OsM glucose

• 1 M NaCl = ? OsM NaCl

• 1 M MgCl2 = ? OsM MgCl2

• Osmolarity of human body ~ 300 mOsM

• Isosmotic, hyperosmotic, hyposmotic

Tonicity• Physiological term describing volume change of cell

if placed in a solution

• Always comparative. Has no units.– Isotonic– Hypertonic– Hypotonic

• Depends not just on osmolarity (conc.) but also on nature of solutes (penetrating vs. nonpenetrating solutes)

Penetrating vs. Nonpenetrating Solutes

• Penetrating solute: can enter cell (glucose, urea)

• Nonpenetrating solutes: cannot enter/leave cell (sucrose, NaCl*)

• Determine relative conc. of nonpenetrating solutes in solution and in cell to determine tonicity.– Water will move to dilute nonpenetrating solutes– Penetrating solutes will distribute to equilibrium

Fig 5-31

IV Fluid Therapy

2 different purposes:– Get fluid into dehydrated cells or– Keep fluid in extra-cellular compartment

Resting Membrane Potential

IC and EC compartments are in electrical disequilibrium

Review basics of electricity if necessary

K+ is major intracellular cation

Na + is major extracellular cation

Water = conductor / cell membrane =

Electro-Chemical Gradients• Allowed for by cell membrane

• Created via–Active transport–Selective membrane permeability to certain

ions and molecule

• Membrane potential = unequal distribution of charges across cell membrane

Fig 5-32

• All cells have it

• RestingResting cell at rest (all cells)

• Membrane Potential Membrane Potential separation of charges creates potential energy

• DifferenceDifference difference between electrical charge inside and outside of cell (ECF by convention 0 mV)

• Measuring membrane potential differences

RestingResting Membrane Potential Membrane Potential DifferenceDifference

Fig 5-33

Resting Membrane Potential Mostly Due to Potassium

Cell membrane – impermeable to Na+, Cl - & Pr –

– permeable to K+

K+ moves down concentration gradient (from __________ to ____________ of cell)

Excess of neg. charges inside cell

Electrical gradient created

Neg. charges inside cell attract K+ back into cell

Equilibrium Potential for K+

Eion= Membrane potential difference at which movement down concentration gradient equals movement down electrical gradient

In other words: At Eion: electrical gradient equal to and opposite concentration gradient

EK+ = - 90 mVFig 5-34

Equilibrium Potential for Na+

• Assume artificial cell with membrane permeable only to Na+

• Redistribution of Na+ until movement down concentration gradient is exactly opposed by movement down electrical gradient

ENa+ = + 60 mV

Fig 5-35

Resting Membrane Potential

Reasons:• Membrane permeability: K+ >

Na+ at rest

• Small amount of Na+ leaks into cell

• Na+/K+-ATPase pumps out 3 Na+ for 2 K+ pumped into cell

In most cells between -50 and -90 mV (average ~ -70 mV)

StimulusStimulus

DepolarizationDepolarization

RepolarizationRepolarization

HyperpolarizatioHyperpolarizationn

Changes in Ion Permeability• lead to change in membrane potential• Terminology:

Fig 5-37

Explain• Increase in membrane potential

• Decrease in membrane potential

• What happens if cell becomes more permeable to potassium

• Maximum resting membrane potential a cell can have

Insulin Secretion• Membrane potential changes play

important role also in non-excitable tissues!

• -cells in pancreas have two special channels:– Voltage-gated Ca2+ channel– ATP-gated K+ channel

Fig 5-38

Cells Avoid Reaching Glucose Equilibrium

???

Running problem: Cystic Fibrosis