Header to be Filled in by Amy Gelban

SELF-STUDY:
MEMBRANE FUNCTION AND STRUCTURE AND AN INTRODUCTION TO
MEMBRANE TRANSPORT OF SOLUTES
Tom Shannon
tshannon@rush.edu
AIM, Google, Yahoo: tshanno
Resource Material: (Recommended reading assignments)
Reading: Berne and Levy Principals of Physiology, 4th Edition, p. 3-18
Lecture objectives:
1. Understand basic membrane structure: this includes the lipid bilayer, embedded proteins and
proteins associated with the membrane on the internal and external surface.
2. Understand the concepts of polar and non-polar molecules and of electrolytes (ions) and
non-electrolytes. Understand the forces that govern their interactions and how they move.
3. Learn the mechanisms by which solutes move in solutions and across membranes.
4. Understand the general effects of distance and molecular size on the rate of solute movement
by diffusion.
5. Learn Ficks Law of diffusion, and thereby understand what determines flux in the situations
that this law describes.
6. Distinguish between simple diffusion across the bilayer and protein-mediated transport.
7. List the basic types of protein-mediated transport.
8. Distinguish between simple facilitated diffusion and active transport.
9. Describe the differences between channels and carriers.
10. Understand what is meant by specificity, saturation and competition for facilitated (proteinmediated) diffusion.
11. Understand what is meant by primary and secondary active transport.
12. Know the differences between co-transporters and counter-transporters (also called
exchangers).
Key Words:
active transport
exocytosis
carriers
facilitated diffusion
channels
flux
co-transporter
Na+/K+ pump (or ATPase)
competition
permeability
counter-transporter
primary active transport
diffusion
saturation
electrical migration
specificity
endocytosis

I.

About this Self-Study

This self-study is more or less the first half of the lecture that I gave in the Cellular and
Molecular Block in September. In that respect it is more of a review. Though I do expect you to
know the material it contains I will not be testing you over it directly.
When I write test questions, I generally flip open the notes and start writing. I will not be
looking at this self study and no questions will be asked directly over the material. For instance,
I wont ask, What is a primary active transporter? But when I say something is a primary
active transporter you need to know what that means and be able to use what you know about
them to solve problems.
It is, therefore, my judgment that if you dont understand this material and remember it, you will
not be able to understand the lectures which I will give in this block. Because of that, I would
encourage you to review the material and make sure you understand it. I will assume that you
have done so before I start upon building upon it.

II. Movement of Solutes in Solution and Across Membranes

1. Movement of Solutes: General Mechanisms. Three basic mechanisms by which solutes
move are briefly considered here. These are: bulk flow, diffusion and electrical
migration. Movement of solutes across membranes will be considered in greater detail
shortly.
a.

Bulk flow is the bulk movement of solutions by hydrostatic pressure. Clearly both
solutes and solvents (almost always water in physiological situations) move (so this
is not the movement of solutes in solutions, but rather of solutions themselves).
Flow is proportional to the pressure difference. We will only briefly consider bulk
flow further in these lectures; it is noted here mostly for the sake of completeness.

b.

Diffusion: Diffusion results from the random thermal motion of molecules, but will
result in directed (net) movement of solutes when concentration differences exist.
Diffusion moves solutes from regions of higher concentration to regions of lower
concentration, eventually leading to uniform concentrations (if unopposed by other
processes). See Figure 1.3.

Diffusion takes time to change concentrations, and the amount of time depends on
the distances involved and the size of the molecules that are diffusing. Larger
molecules diffuse more slowly than smaller ones. In addition, for any particular
molecule the average time needed to travel a particular distance, x, varies as x2 (i.e.,
the distance squared). It only requires roughly 10 msec for a typical small
molecule to diffuse 5 microns in an aqueous solution. However, for this molecule to
diffuse 50 microns would require 100 (102) times longer, i.e., 1 second. To diffuse 1
mm would require 400 seconds. Understanding this helps to explain many cellular
and subcellular structures that rely on diffusion for the movement of solutes
distances must be kept small to achieve rapid movement of solutes. This is very
evident in the internal structure of skeletal and cardiac muscle.
Diffusion of solutes will be considered further below, as will diffusion of water
(called osmosis).
c.

2.

Electrical Migration: ions (also called electrolytes) are solutes with net charge. Ions
move (migrate) in response to an electric field. Obviously ions also diffuse, but,
unlike non-electrolytes, electrical forces must also be considered in the movement of
ions. The movement of ions is also often called electrodiffusion. We will consider
this phenomenon in more detail in the musculoskeletal block but you should be
aware of it.

Movement of Solutes Across Membranes: Our primary concern in this section is the
movement of solutes across membranes, even though this can not be completely divorced
from the movement of solutes in solution.
a.

Diffusion, flux and permeability: The most basic mechanism by which solutes cross
membranes is diffusion. To better understand the factors which determine the rate at
which solutes diffuse we need to define flux. When there is a net movement of a
substance (solute) from one point to another we say there is a flux of the substance.
Flux is defined as the quantity that moves over a specified period of time, i.e., Flux
= Quantity/Time

Ficks Law (here we are considering a somewhat simplified version of the Fick
equation that some of you may already be familiar with) basically describes the flux
across a membrane of a solute from diffusion in terms of permeability (P), the
membrane area (A), and the concentration difference (C) across the membrane.
Ficks Law can be written as:

Flux = P x A x C
The permeability, P, is different for different substances. Some solutes (mostly nonpolar, lipid soluble solutes) cross the membrane by dissolving in the bilayer and
diffusing across it. In such cases, the size of the molecule (smaller molecules are
more permeable than larger ones, all else being equal) and its lipid solubility
determine the permeability (lipid solubility is of greatest importance). Some
clinically important examples of substances with high lipid solubility are codeine,
xylocaine and novocaine (local anesthetics) and alcohol. Also note that dissolved
gas molecules, most importantly oxygen molecules (O2) and CO2, have a reasonably
high solubility in lipids and therefore primarily simply diffuse across the lipid
bilayer.
Ions almost exclusively cross the membrane with the help of membrane proteins.
This will be considered in greater detail shortly under the heading of proteinmediated transport. However, in the case of ionic channels, we are still considering
diffusion, but now through aqueous pores formed by transmembrane proteins
(channels). In these cases, many factors influence the permeability of the particular
ionic species. These include: the number of channels present, the conductance of the
open channel (basically how many ions it allows to pass per second) and the open
probability of the channels (i.e., what fraction of the channels are open). All such
issues will become clearer in future lectures.

TAKE HOME MESSAGE

For Movement of Solutes (up to this point)
1. Know the basic ways that solutes move in solution and across membranes.
2. Understand Ficks Law of diffusion and the factors involved in this law

3. Know the effects of solute size and of distance on the rate of solute movement by
diffusion.
4. Understand the basic factors that determine membrane permeability to various
solutes; e.g., solubility of the substance in the lipid bilayer, solute size, presence
of channels or other forms of protein mediated transport, etc.

b.

Protein Mediated Transport: Many substances enter or leave cells by means of

specific carriers, channels or active transporters that are intrinsic membrane proteins.
This form of transport is usually referred to as protein mediated transport. There
are two basic categories of protein mediated transport; these are: facilitated
diffusion and active transport. These two basic categories are themselves broken
down into different subcategories as described below.
1.

Facilitated diffusion (also called facilitated transport) does not involve any use
of metabolic energy (unlike active transport, see below). There are two basic
categories of facilitated diffusion; these are transport via carriers and via
channels.
a. Channels: There are also many types of channels and not all are protypical,
e.g., for the transport of water across the membrane (these channels are
called aquaporins, although water can also pass through the bilayer in many
membranes). All channels are characterized by a pore that spans the
membrane (see Figure 1.6). In most cases, the channel can exist in at least
two states (conformations of the channel protein). These are the open state
(in which the pore is open and allows the passage of the substances that can
cross the membrane through this pore) and the closed state (in which the
pore is closed, allowing nothing the cross the membrane). Channels also
show 3 other important characteristics which distinguish them from simple
diffusion; these are: 1) specificity, 2) saturation and 3) competition. Since
these are characteristics that are shared by carrier mediated transport,
discussion of them will be postponed until carriers have been discussed.
Important characteristics of several types of ionic channels will be discussed
in future lectures.
b. Carriers: carriers or carrier-mediated facilitated diffusion can be
distinguished from channels in a variety of ways. Like channels, these are
protein molecules embedded in the membrane and generally span the
membrane. The carrier molecule binds one or more molecules of the solute
to be transported and changes its conformation to allow this solute to cross
the membrane. The basic idea is illustrated in Figure 1.5.

FIGURE 1.5 Carrier

Mediated Passive Transport
(Berne & Levy, Fig. 1-10)

FIGURE 1.6 Generalized

Ionic Channel
(Berne & Levy, Fig. 1-10)

The
simplest way to think of a carrier molecule is as a transmembrane protein
that undergoes repetitive (and numerous) spontaneous conformational
changes. Two conformations must be considered: in one conformation a
binding site (or sites) for the transported solute is exposed to the
extracellular fluid; in the other conformation the binding site is exposed to
the intracellular fluid. This is illustrated in cartoon-fashion in Figure 1.5.
The transported solute is more likely to bind to the carrier when the binding
site is exposed to the side of the membrane where the solute is more highly
concentrated. Similarly, the solute is more likely to dissociate from the
carrier when the binding site is exposed to the side of the membrane where
the solute is less concentrated. Because of this, the effect is to move the
solute from the region of higher concentration to lower concentration. At
most, the concentration on the two sides of the membrane can become
equalized. So the carrier accomplishes nothing that simple diffusion could
not have (eventually) accomplished. But you must remember that the
transported solutes have an EXTREMELY low permeability through the
lipid bilayer. Thus carrier-mediated facilitated diffusion greatly increases
the rate of transport across the membrane.
An additional point: channels (when open) typically transport millions or
tens of million of molecules (ions) per second; carriers typically transport
thousands of molecules per second.
c. Some Important Characteristics of Carrier-Mediated Transport: Carrier
mediated transport differs from simple diffusion in several important ways:
1.

Specificity: Each type of carrier protein is specialized to transport a

specific solute (e.g., glucose, fructose, amino acids, etc.), or a few
closely related chemical compounds. Thus each type of carrier shows
specificity in terms of the substances it can transport.

Clinical correlation:
(It is often difficult for students to see membrane biochemistry and
physiology as being relevant to the student as a future physician.
Therefore, whenever possible, I have inserted Clinical Correlations
periodically at appropriate times within my notes. However, this is
not a pathology course and you are NOT responsible for clinical
correlation material within my notes unless it is a disease covered as a
Case Study or in a workshop.)
Some hereditary diseases involve defects in specific carrier-mediated
transport systems. For example, cysteinuria (elevated cysteine in the
urine) involves defects in cysteine carriers in the membranes of the
nephrons of the kidneys. Normally the kidneys remove (reabsorb)
cysteine from the fluid passing through the kidney to form urine and
return this essential amino acid to the blood. With a defect in the
cysteine carrier, large amounts of cysteine remain in the tubular fluid
that becomes urine. Since cysteine is relatively insoluble in water, it
tends to precipitate, and thereby cause kidney stones.
2.

Saturation: Each carrier molecule is limited to transporting only a

certain number of its selected molecules per second (typically roughly
1000 to 10,000). In addition, the number of carriers per cell is also
limited. It is therefore clear that there is a limit to how much solute
any particular carrier system in any particular cell or tissue can
transport; this is referred to as saturation. Unlike simple diffusion,
where transport increases linearly as concentration difference (C)
increases, carrier-mediated transport will display a maximum (called
the transport maximum, Tm), with further increases in concentration
not leading to further increases in transport. This is illustrated in
Figure 1.7.

3.

Competition: competition refers to the fact that several closely related

chemical compounds may compete for transport by a single type of
carrier. An example of this is the glucose/fructose carrier in the lumen

of the intestine. If the concentration of fructose increases in the

intestinal lumen then the transport of glucose will decrease, since the
same carrier can transport either solute.
d. Channels also display all of the 3 characteristics just described however,
these characteristics are in some cases not very important to the natural
function of channels.
Commentary:
(Occasionally I will insert Commentaries into my notes. These are
present to supply additional information, usually addressing questions which
students have asked multiple times in the past as Ive taught the material.
The commentaries are, therefore, often useful for students who wish more in
depth information. However, please note that you are NOT responsible for
the materials in commentaries scattered throughout my notes. These are
FYI, only.)
Specificity is important to the function of almost all ionic channels. In some
cases, this specificity is so potent that the selected ion will outnumber any
other ions crossing the membrane through the channel by more to 100 to 1.
In other cases, ionic channels may be much less selective (e.g., simply
selecting for cations rather than anions).
Saturation is also usually observed in ionic channels, but its importance
under natural physiological circumstances is often very limited. In the first
place, many ionic channels only show saturation at concentration levels of
the transported ion or ions that are far larger than the concentrations that are
ever encountered under natural conditions. It is also important to recognize
that ionic concentrations within the body (both intracellular and
extracellular) are normally maintained within a very narrow range. This
range is usually a very small variation in comparison to, for example,
glucose concentrations that occur in the gut or in the tubules of the kidneys.
Finally, competition is usually not of much importance to ionic channels
under normal physiological conditions, mostly because (as already noted)
ionic concentrations in the body do not vary over wide ranges.
2.

Active Transport: Active transport is defined as transport that can proceed

against an electrochemical potential difference, or simply can move the
transported solute 'uphill from a region of lower concentration to a region of
higher concentration. To accomplish this, a source of metabolic energy must be
available. Two general types of active transport are distinguished on the basis
of whether or not they directly utilize metabolic energy; these are primary
active transport and secondary active transport.
a. Primary Active Transport directly utilizes metabolic energy in the transport
process. The membrane protein associates the movement of the transported

solute (or solutes) with the hydrolysis of ATP. These transporters are
frequently called ATPases of simply pumps. Some examples include:
The Na+/K+ pump or ATPase of most cell membranes. This molecule
uses the splitting of a single molecule of ATP to move 3 Na+ ions out
of the cell and to move 2 K+ ions into the cell. In both cases, this is a
move from a lower concentration to a higher concentration. This
pump is responsible for maintaining the concentration gradients for
both Na+ and K+ across the cell membrane (high extracellular Na + and
high intracellular K+).
The Ca2+ pump of the endoplasmic reticulum of most cells and the
sarcoplasmic reticulum of muscle cells. This pump is responsible for
sequestering Ca2+ within these organelles, which can then be released
by various cellular processes (e.g., the release of Ca 2+ from the SR
initiates contraction in muscle). The Ca2+ pump is also located in the
surface membrane of many cells (e.g., cardiac muscle cells). In this
location it moves Ca2+ from the cytoplasm to the extracellular fluid
and helps to maintain very low cytoplasmic resting concentration of
Ca2+.
The H+ pump of the basolateral membrane of specialized stomach
cells (parietal cells) results in the secretion of HCl during digestion.
H+ pumps also occur in some tubular cells in the kidney.
b. Secondary Active Transport can also proceed against electrochemical
gradients (i.e., uphill transport), but without direct coupling to the
hydrolysis of ATP. Instead, in the case of secondary active transport, the
transport is indirectly linked to ATP hydrolysis. This is accomplished by
coupling the uphill movement of the transported solute to the downhill
movement of another solute (usually Na+), whose concentration gradient
was established by primary active transport (e.g., there is energy stored in
the concentration gradient for Na+, which can be used to transport other
solutes). There are basically two types of secondary active transport which
are referred to as co-transporters and counter-transporters (also called
exchangers).
Co-transporters move both solutes (i.e., the solute whose gradient was
determined by primary active transport e.g., Na+ and the solute that the
transporter wants to move against it electrochemical gardient) in the same
direction. For example, The Na+/glucose cotransporter of absorptive cells
(enterocytes) in the intestinal lumen couples the movement of a single
glucose molecule into the cell to the movement of one Na + ion into the cell.
It is capable of moving glucose against its concentration gradient by
coupling this movement to the movement of Na+ down its electrochemical
gradient. In other words, this cotransporter uses the energy of the Na +
gradient to concentrate glucose in the enterocyte.

Counter-transportes (or exchangers) do something similar, but the solutes

move in opposite directions. For example, the Na+/Ca2+ exchanger of the
cardiac and smooth muscle cell membrane couples the downhill movement
(into the cell) of 3 Na+ ions to the uphill movement (out of the cell) of 1 Ca2+
ion. The Na+/Ca2+ and Na+/H+ exchangers are important to cellular function.
Figure 1.8 schematically illustrates both cotransport and countertransport.
3.

Vesicle Mediated Transport: The last mechanism by which solutes are

transported across membranes is vesicular transport. This includes both
exocytosis and endocytosis.
In exocytosis, intracellular solutes are encapsulated (trapped) within membrane
vesicles. These vesicles fuse with the membrane (usually in response to specific
stimuli) and release their contents into the extracellular fluid. Examples include
synaptic transmitters, hormones and some digestive enzymes.
Endocytosis is essentially the reverse process. Extracellular substances are
trapped within vesicles that are formed by invaginations of the surface
membrane. The endocytotic vesicle pinches off from the cell membrane and
then typically fuses with a lysosome causing it to release its contents.

Another form of endocytosis that is often distinguished is called receptormediated endocytosis. In this case the material to be transported first binds to a
receptor and then the substance-receptor complex is ingested by endocytosis.
Examples of substances that are frequently transported into the cell in this way
are iron and cholesterol.

TAKE HOME MESSAGE

For Protein-Mediated Transport
1. Understand that most of the solutes that cross the cell membrane do so with
the help of membrane protein molecules. This is what is meant by protein
mediated transport.
2. Know the differences between simple facilitated diffusion and active
transport i.e., active transport requires the utilization of metabolic energy
3. Understand the differences between channels and carriers.
4. Understand the differences between primary and secondary active transport.
5. Know what distinguishes co-transporters from counter-transporters (also
called exchangers). Both are examples of secondary active transport.
Understand the Na+/Ca2+ exchanger.
6. Know the basic characteristics of vesicle mediated transport, including
excocytosis and endocytosis.