Human Physiology

Chapter 6: Movement of molecules across cell membranes John Paul L. Oliveros, MD

Molecules of any substance are in a continuous state of movement or vibration y The warmer the substance is, the faster its molecules move y The average speed of the thermal motion depends on the mass of the molecule
y

Diffusion

Water= 2500km/h Glucose= 850km/h

In solutions, molecules cannot travel very far before colliding with other molecules y The movement of molecules are random y The random thermal movement of molecules will redistribute solutes in a solution from regions of higher concentration to regions of lower concentration y Diffusion: movement of molecules from one location to another due to random thermal motion
y

Diffusion

Diffusion

Diffusion
y

Flux
amount of material crossing a surface in a unit of time

Net Flux
The difference between the 2 oneway fluxes Determines the net gain/loss of molecules from compartments separated by a membrane Always occur in the direction from higher to lower concentration

Distribution Equilibrium
The two one-way fluxes are equal in magnitude but opposite in direction Net flux is equal to zero No further changes in the concentration of a substance in the 2 compartments will occur

Diffusion
y

Properties of diffusion:
Three fluxes can be determined at any surface (2 opposite one-way fluxes; one net flux) The net flux is the most important component in diffusion since it is the net amount of material transfered from one location to the other The direction and the magnitude of the net flux are determined by the concentration difference
x The net flux always proceeds from regions of higher concentration to regions of lower concentration x The greater the difference of concentration between any two regons the greater the magnitudeof the net flux

Diffusion
y

Factors determining the magnitude of the net flux at any given concentration difference
Temperature
x Inc. Temp inc. Speed of molecular movement inc. Net flux

Mass of the molecule

x Inc. mass dec. Speed of mol. Mov. dec net flux

Surface area
x Inc S.A. inc space for diffusion x Air > Water inc net flux

Medium of which the molecules are moving

Diffusion
y

Diffusion rate vs Distance

Diffusion times increase in proportion to the square of the distance over which the molecules diffuse

265 days

Diffusion
y

Diffusion through membranes

Magnittude of the net flux is directly proportional to the difference in concentration across the membrane, the surface area of the membrane, and the membrane permeability constant

Diffusion
y

Diffusion through the lipid bilayer

Major limiting factor of diffusion across membrane Polar molecules disolve into cells slowly or not at all
x Organic molecules

Nonpolar molecules dissolve rapidly

x Can dissolve in the nonpolar regions of the lipid membrane x Oxygen, carbon dioxide, fatty acids, steroid hormones

Diffusion of Ions through Protein Channels Ions (Na+, K+, Cl -, Ca++) diffuse faster in cells with more integral membrane proteins Integral proteins form channels Selectivity on passage of ions
x Diameter x Polarity of surface

Diffusion

Diffusion
y

Role of Electric Forces on Ion Movement

Membrane potential
x Separation of charges across the cell membrane x electric force that influences movemnt of ions across membranes x Same sign elcetric charges repel each other x Different sign charges attract each other x Most cellss are electrically negative atract + charged ion

Electrochemical gradient
x Electrochemical difference across a membrane x Concentration difference + electrical difference (membrane potential

Diffusion
y

Regulation of Diffusion through ion channels

Channel gating
x Process of opening and closing ion channels

Patch clamping
x Technique that helped study ion channels

Ligand sensitive channels

x Binding of specific molecules to channel proteins produces allosteric or covalent changes of the protein

Voltage-gated channels
x Changes in the membrane potential causes movement of charged regions of the channel proteins

Mechanosensitive channels
x Stretching the membrane affect the conformation of some channel proteins

Mediated Transport Systems

y

Transporters/carriers
Integral membrane proteins that mediate the passage of large or polar molecules and nondiffusional movement of ions

Factors determining magnitude of solute flux

1. Extent to which transporter binding sites are saturated The number of transporters in a membrane Rate of conformational change in the transport protein

2.

3.

Mediated Transport Systems

y

When transporters are reportedly almost saturated, the maximal transport flux depends on the rate of conformational change of the transporter to transfer its protein from one surface to the other

Mediated Transport System

y

Facilitated Diffusion
Uses a transporter to move solutes downhill, from a higher to lower concentration until concentration between the 2 sides are the same Really doesnt involve diffusion but end results are the same No energy is involved E.g. Glucose transport

Mediated Transport Systems

y

Active Transport
Uses energy to move a substance against its electrochemical gradient (uphill) Requires binding of the substance to the transporter in the membrane AKA pumps Also exhibits specificity and saturation

Active transport
Needs continuous input of energy
1. Alter the affinity of the binding site on the transporter; higher affinity when facing one side of the membrane than the other Alter the rates at which the binding site on the transporter is shifted from one surface to the other

2.

Two types:
x Primary active transport x Secondary active transport

Mediated Transport System

y

Primary active transport

Transporter: ATPase ATP breakdown and phosphorylation of ATPase energy

Events during active transport

1. Exposure of binding site to ECF 2. Binding of solute to the binding site 3. Removal of the PO4 group of the transporter 4. Release of solute to ICF 5. Rephosphorylation of binding site as it agian exposed to ECF

Mediated Transport Systems

y

Primary Active Transport

Na, K-ATPase
x Present in all plasma membranes x High intracellular K+ and low intracelluilar Na+ x 1 ATP 3 Na+, out x , 2K+ in

Ca-ATPase
x In plasma membrane and endoplastic reticulum

H-ATPase
x In PM, mitochondria and lysosomes

H, K-ATPase
x In acid secreting cells of stomach and kidneys

Mediated Transport System

y

Secondary Active Transport

Use ion concentration gradient as energy source

Events during secondary active transport

1. Altering the affinity of the binding site for the solute 2. Altering the rate of at which the binding site is shifted from one surface to the other 3. Protein allosteric modulation due to ion binding

Mediated Transport System

y Secondary Active

Transport
Cotransport
x Solute moves with same direction as ion

Countertransport
x Solute move opposite direction of ion

Mediated Transport System

y

Secondary active transport Na+, Ca++ countertransport Digitalis

x Inhibits Na+,K+-atpase in heart muscle cells x Increase in IC Na+ x Increase in IC Ca++ x Increase in force of contraction of heart muscles

Mediated Transport System

Mediated Transport system

Mediated Transport System

Osmosis
y

Water
Small polar molecule 0.3 nm in diameter Plasma membranes 10x more permeable to water than artificial membranes Aquaporins:
x Membrane proteins that form channels where water can diffuse x Number differs in different membranesa x Can be alterted in response to various signals

Osmosis
Net diffusion of water across membranes Additon of solute decreases concentration concentration difference flux Mol Wt of H20 = 18 1L H20 =1kg Conc. Of H20 in pure H20 = 1000/18 = 55.5M 1 molecule of solute will displace1 molecule of H20
x Dec in H20 conc= conc of solute x 1M of glucose = 54.5 M H20

Osmosis

The degree to which H20 conc is decreased by addition of a solute depends upon the number of particles (molecules/ions) of solute in a solution and not upon the chemical nature of the solute
e. g. Concentration of 1 mol glucose solution = 1mol AA soultion= 1 mol urea solution

A molecule that ionizes in a solution decreases the water concentration in proportion to the number of ions formed
e.g. 1 M of MgCl++ lowers water conc 3x than 1 M glucose

Osmosis
y

Osmolarity
Total solute concentration of a solution 1 osm = 1 molecule of particle in a solution 1M of glucose = 1osm I M of NaCl = 2 osm The higher the osmolarity, the lower the water concentration

Osmosis
y

Membrane impermeable to solutes but permeable to water

Just like plasma membrane Equilibrium:
x Equal concentrations in both compartments x Volume in expands in the compartment with more solutes

if compartments are infinitely expandle, net transfer doesnt create a pressure gradient

Osmosis
y

Membrane impermeable to solutes but permeable to water but nonexpandable/limited expansion

H20 moves to compartment with more solutes increase in pressure of compartment oppose net water entry Osmotic pressure: the pressure that must be applied to the solution to prevent the net flow of H2O into the solution

Osmosis
y

Extracellular osmolarity and cell volume 85% of EC solutes are Na++ and ClNa++ moved out by Na, K-ATPase pump Cl- moved out by secondary activetransport pumps Both ions behave as nonpenetrating solutes

Intracellular K+ and organic molecules Organic molecules are large and polar, thus are non-penetrating K+ is moved preferably moved into cells by Na, K-ATPase pump Both intracellular extracellular osmolarity are kept at 300 mOsm

Osmosis

Endocytosis and Exocytosis

y

Endocytosis:
Folding of regions of PM small pockets IC vesicles

Exocytosis:
IC vesicles fusion with PM release of contents EC

Endocytosis
y

Pinocytosis (cell drinking)

Fluid endocytosis
x Enclosure of a small volume of ECF

Adsorptive endocytosis
x Molecules bind to membrane CHONs and are carried along with ECF inside the cell when membrane invaginates

Phagocytosis (cell eating)

Large particles are engulfed by cells PM folds around the surface of the particle so that little ECF is enclosed within the vesicles

Exocytosis
y

Funtions:

To replace portions of PM removed during endocytosis Route for impermeable CHONs getting outside cell y New CHONs endoplasmic reticulum processing in golgi apparatus vesicles plasma membrane released to ECF

Release triggered by stimuli that leads to an increase in cytostolic concentration in cells y Stimuli opens Ca++ channels in PM and/or membranes of IC organelles y Increase in Ca++ activates CHONs requiredfor the vesicle membrane to fuse with the PM and secrete contents EC y For rapid secretion of materials in response to stimulus
y

Epithelial Transport
y y

Basolateral membrane:
Adjacent to network of blood vessels Opposite apical membrane

Epithelial cells
Line hollow organs and tubes Regulate absorption and secretion of substances across membranes

Luminal/Apical membrane
Surface facing a hollow or fluid filled chamber

2 pathways crossing the epithelium

Paracellular pathway
x Diffusion between adjacent cells x Limited due o tight junction membranes

Transcellular pathway
x Movement across cell from apical to basal membrane

Epithelial Transport
y

Transcellular Transport
Through diffussion and mediated transport Different transport and permeability characteristics between apical and basement membranes Substances undergo active transfusion across the overall epithelial layer e.g. GI tract, kidneys, glands

Epithelial Transport

Glands
y

Types of Glands
Exocrine gland
x Secretions flow through the ducts and are discharged into the lumen of an organ or the surface of the skin x e.g. Sweat glands, salivary glands

Glands
Secrete specific substances into the extracellular fluid or the lumen of ducts in response to appropriate stimuli Formed during embryonic development by the infolding of the epithelial layer of an organs surface

Endocrine gland
x Ductless glands\ x Secretions are released directly on the interstitial fluid surrounding the gland cells x Secretions then diffuses into the blood carrying it to all of the body

Glands
y

Endocrine glands
Hormones
x Major class of chemical messengers

Non-hormonal organic substances

x e.g. Liver: glucose, A.A., fats, CHONs,

Types of glandular secretions

Organic material
x Synthesized by cells

Salts and water

x From blood supplying the tissue

Glands
y

Glands
Undergo low basal rate of secretion Signal (nerve signals, hormones) augnmentation of secretions Mechanisms in increasing secretion: 1. increase rate of synthesis by increasing enzyme 2. providing Ca ++ for exocytosis 3. altering pumping rates of transporter or opening ion channels
y

Glands
Volume of secretion increased by increasing Na+ pump activity or controlling the opening of Na+ channels in the PM Increase in Na+ in the epithelium increases flow of H20 by osmosis