U N I T II
Textbook of Medical Physiology, 11th Edition
Chapter 4:
Transport of Substances Through
the Cell Membrane
Slides by Thomas H. Adair, PhD
GUYTON & HALL
Copyright © 2006 by Elsevier, Inc.
Lipid Bilayer:
• barrier to water and water-soluble substances
CO2
ions
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glucose
H2O
N2 O2
urea
halothane
Permeability coefficients (cm/sec)
(** across an artificial lipid bilayer)
water
urea
glycerol
glucose
ClK+
Na+
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10-2
high permeability
10-4
10-6
10-8
10-10
10-12
low permeability
Molecular Gradients
inside
outside
(in mM)
(in mM)
Na+
K+
Mg2+
Ca2+
H+
HCO3ClSO42PO3-
14
140
0.5
10-4
(pH 7.2)
10
5-15
2
75
protein
40
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142
4
1-2
1-2
(pH 7.4)
28
110
1
4
5
Proteins:
• provide “specificity” to a
membrane
• provide “function”
ion channels
K+
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carrier proteins
Diffusion
• occurs down a concn.
gradient
• no mediator or involves
a “channel” or “carrier”
• no additional energy
Figure 4-2; Guyton & Hall
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Active Transport
• occurs against a concn.
gradient
• involves a “carrier”
• requires ENERGY
Simple Diffusion
(a) lipid-soluble molecules move readily across the membrane
(rate depends on lipid solubility)
(b) water-soluble molecules cross via channels or pores
(a)
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(b)
Ion Channels
Characteristics:
ungated
• determined by size, shape, distribution of charge, etc.
gated
• voltage (e.g. voltage-dependent Na+ channels)
• chemically (e.g. nicotinic ACh receptor channels)
in
Na+ and
Na+
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ions
other
out
How to Study?
• “Patch Clamp”
•
Nobel Prize in
Physiology & Medicine
-1991
Extracellular
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Inside Cell
Ion Channels
in
out
Na+
Figure 4-5; Guyton & Hall
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Ionophores
- hydrophobic molecules that dissolve in lipid bilayers
and increase permeability to specific inorganic ions.
Ionophores mediate passive transport.
1. Mobile ion carriers (e.g. valinomycin, A23187)
• “pick up” ion from one side of the membrane and deposit it
on the other
2. Channel formers (e.g. gramicidin A)
• form ion-permeable pores in the membrane
• transport 1000x more ions per unit time than mobile ion carriers
Valinomycin and gramicidin A are made by certain
bacteria and have been used as antibiotics.
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Simple vs. Facilitated
simple diffusion
rate of diffusion  (Co-Ci)
rate of
diffusion
Vmax
Tm
facilitated diffusion
Concn of substance
What limits maximum rate of
facilitated diffusion?
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Facilitated Diffusion
(also called carrier mediated diffusion)
Rate of diffusion is limited by
− Vmax of the carrier
protein
− the density of carrier
proteins in the membrane
(i.e., number per unit area)
Figure 4-7; Guyton & Hall
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Factors that affect
the net rate of diffusion:
1. Concentration difference (Co-Ci)
net diffusion  D (Co-Ci)
Figure 4-8; Guyton & Hall
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Net Diffusion
A
B
Can a molecule diffuse from side B to
side A?
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2. Electrical potential (EMF)
+
-
- - - - -- - -- -- - - - +-- When will the
- - - -- negatively charged
-- - - - molecules stop
-entering the cell?
- -
The Nernst potential (equilibrium potential) is the theoretical
intracellular electrical potential that would be equal in magnitude but
opposite in direction to the concentration force.
EMF (mV) = ±61 log (Co / Ci)
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3. Pressure difference
• Higher pressure results in increased energy available to
cause net movement from high to low pressure.
Figure 4-8; Guyton & Hall
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Osmosis:
- Net diffusion of water -
Osmosis occurs from pure water toward a water/salt solution.
Water moves down its concn gradient.
Figure 4-9; Guyton & Hall
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Osmotic Pressure:
the amount of pressure required to counter osmosis
Osmotic pressure is
attributed to the
osmolarity
of a soln
Figure 4-10;
Guyton & Hall
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Major determinant of osmotic pressure
A
B
100 g
in 1 L
1000 g
in 1L
Solute A
Mw = 100
Solute B
Mw = 1000
Which solution has the greatest osmolarity?
Which has the greatest molar concn?
Which has the greatest number of molecules?
(6.02 x 1023 particles)
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Relation between osmolarity and molarity
mOsm (millisomolar) =
or mOsm/L
index of the concn
of particles per liter soln
mM (millimolar)
or mM/L
index of concn of
molecules per liter soln
=
150 mM NaCl = 300 mOsm
300 mM glucose = 300 mOsm
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Estimating Plasma Osmolarity
• Plasma is clinically accessible.
• Dominated by [Na+] and the associated anions
• Under normal conditions, ECF osmolarity can be roughly
estimated as:
POSM = 2 [Na+]p
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270-290 mOSM
Isotonic and Isosmotic
150 mM NaCl
300 mOsm NaCl
0.9% NaCl
300 mM glucose
300 mOsm glucose
5% glucose
300 mM urea
300 mOsm urea
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Isotonic
Isosmotic
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Steady-state cell volume
is dependent upon the concentration of impermeant particles
in the extracellular fluid (e.g. Na+, K +, protein-)
Permeant particles cause only transient changes in cell
volume (e.g. urea, glycerol)
Time course of the change in cell volume is dependent on
the permeability of the particle
higher permeability = more transient the change
urea > glycerol
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Example:
300 mOsm
NaCl
200 mOsm glycerol
200 mOsm NaCl
Shrink then swell
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Swell
Shrink
Time course??
Example:
300 mOsm
NaCl
200 mOsm
Urea
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Swell
Shrink
No change??
Clinical Abnormalities
of Fluid Volume Regulation
Hypernatremia (increased plasma Na):
• increased water loss
• excessive sweat loss
• central or nephrogenic diabetes insipidus
**decreased ADH secretion or responsiveness to ADH
Hyponatremia (decreased plasma Na):
• large water ingestion
• Syndrome of Inappropriate ADH Secretion (SIADH)
**too much ADH leads to water retention, hyponatremia,
and excretion of concentrated urine.
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Active Transport
Primary Active Transport
• molecules are “pumped” against a concentration
gradient at the expense of energy (ATP)
– direct use of energy
Secondary Active Transport
• transport is driven by the energy stored in the
concentration gradient of another molecule (Na+)
– indirect use of energy
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Primary Active Transport
1. Na+/K+ ATPase
• carrier protein located on the plasma membrane of
all cells
• plays an important role in regulating osmotic balance
by maintaining Na+ and K+ balance (inhibition by
ouabain causes cells to swell and burst!)
• requires one to two thirds of cells energy!
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 subunit
• 100,000 MW
• binds ATP, 3 Na+, and 2 K+
 subunit
• 55,000 MW
• function ???
Figure 4-11; Guyton & Hall
Transport is electrogenic but contributes
less than 10% to the membrane potential
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2. Ca2+ ATPase
• present on the cell membrane and the sarcoplasmic
reticulum
• maintains a low cytosolic Ca2+ concentration
3. H+ ATPase
• found in parietal cells of gastric glands (HCl secretion)
and intercalated cells of renal tubules (controls blood
pH)
• concentrates H+ ions up to 1 million-fold
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Saturation
• similar to facilitated diffusion
• rate limited by Vmax of the transporters
Energetics
• up to 90% of cell energy expended for active
transport!
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Secondary Active Transport
- co-transport and counter-transport -
1. Co-transport (co-porters): substance is
transported in the same direction as the “driver”
ion (Na+)
Examples:
outside
Na+
AA
Na+ gluc
inside
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Na+ 2 HCO3-
2. Counter-transport (anti-porters): substance is
transported in the opposite direction as the “driver” ion
(Na+)
Examples:
outside
Na+
Na+
Ca2+
Na+/HCO3-
H+
Cl-/H+
inside
Copyright © 2006 by Elsevier, Inc.
Q: How do cardiac glycosides
increase cardiac contractility?
Glycosides (eg. digoxin) inhibit the Na/K ATPase…
• increase intracellular Na+
• decrease Na+ gradient
• decrease Na+/Ca2+ counter-transport
• increase intracellular Ca2+
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Q: How do cardiac glycosides
increase cardiac contractility?
Na+
+
Na
K+
+
Na
Ca++
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Digoxin has been a
cornerstone for the treatment
of heart failure for decades
and is the only oral inotropic
support agent currently used
in clinical practice.
Transcellular Transport of Glucose / AA
lumen
epithelium
extracellular
fluid
low
high
low
AA
Na+
glucose
Na+
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AA
AA
Na+
K+
glucose
glucose
Na+
K+