Membrane Transport, General Concepts
S G Schultz, University of Texas Medical School, Houston, TX, USA
ã 2013 Elsevier Inc. All rights reserved.
This article is reproduced from the previous edition, volume 2, pp. 627–630, ã 2004, Elsevier Inc.
Glossary
Active transport Transport of a solute against a
chemical (concentration) and/or electrical
potential difference that is directly (primary) or
indirectly (secondary) driven by metabolic
energy.
Carrier Integral proteins that span the membrane
phospholipid bilayer and are capable of binding a
solute(s) and catalyzing translocation from one side
of the membrane to the other.
The term ‘membrane transport’ refers to processes that bring
about the movement of solutes and water across the barrier,
or envelope that surrounds all living cells in the animal and
plant kingdoms. These processes are responsible for two
ubiquitous characteristics of living cells, namely: (1) the ability
to maintain constant, or near constant, intracellular composi-
tions that differ from the extracellular environment, containing
the highly specialized molecules essential for metabolism and
replication and, at the same time, (2) the ability to selectively
exchange matter and energy with that environment.
All cell membranes consist of a double layer of phospholi-
pids oriented so that their electrically charged, hydrophilic
(or water-loving) head projects into the interior and exterior
of the cells, respectively, and their lipid tails, which are hydro-
phobic (or water-fearing), project inward and form an oily
core. Floating in this oily structure are surface or peripheral
proteins that do not extend through the thickness of the bilayer,
and integral proteins that span the bilayer and provide pathways
for direct communication between the intracellular and extra-
cellular compartments. This lipoprotein bilayer model, which
consists of large expanses of lipid studded here and there with
protein, is illustrated in Figure 1.
Exchange of solutes and water across the lipoprotein barrier
takes place through the lipid as well as through integral pro-
teins and can be classified as (1) simple diffusion; (2) diffusion
through pores or channels; and (3) carrier-mediated transport.
The latter may be subdivided into facilitated diffusion (or
facilitated transport), primary active transport, and secondary
active transport.
Simple Diffusion
The simplest form of membrane transport was recognized
more than a century ago by Overton, who noted that the
ease with which a large variety of molecules cross plant cell
membranes is proportional to their solubility in lipids; indeed,
it is the observation that first suggested that the membranes
Channel Integral proteins that span the membrane
phospholipid bilayer and provide water-filled passageways
(pores) for the diffusion of solutes.
Diffusion Flow of a solute from a region of higher to a region
of lower chemical (concentration) and/or electrical potential
driven solely by thermal random motion of solute particles.
Facilitated diffusion Carrier-mediated transport
processes that are not coupled to a supply of
metabolic energy and, thus, can only result in the
equilibration of a transport solute across the membrane.
were composed of lipids. In essence, he suggests that the mole-
cule simply dissolves in the lipid across one surface, passes
through this oily barrier, and exits at the other side. The rate
of this process is given by a modification of a law derived by
Fick in 1855:
Ji ¼ ki Di DCi
where Ji is the rate of diffusion of solute i across the membrane
(in amount of solute per unit time), ki a measure of the solu-
bility of the solute i in oil compared to water (oil:water parti-
tion coefficient), Di the diffusion coefficient of i or the mobility
of i in the lipid, and DCi the concentration difference of i across
the membrane. The product kiDi is often abbreviated as the
permeability coefficient Pi.
Overton demonstrated that a linear relation between Ji and
ki in plant cells and this relation, now referred to as Overton’s
law, has been confirmed repeatedly.
Diffusion through Pores or Channels (Restricted
Diffusion)
Lipid membranes are essentially impermeable to ions and are
only slightly permeable to water. It is now clear that these
highly hydrophilic molecules traverse cell membranes through
integral proteins that form water-filled pores or channels
that span the bilayer. Although the presence of holes in mem-
branes had been speculated as early as the 1850s and were
strongly suggested by the pioneering work of Hodgkin, Huxley,
and Keynes on the squid axon in the 1950s, they were estab-
lished beyond doubt, more recently, by Hille, Armstrong, and
MacKinnon.
Although some use the terms pore and channel inter-
changeably, others prefer to employ the word pore for integral
proteins that are continually open to the two aqueous com-
partments on both sides of the membrane (using the analogy
of an open pipe) and reserve the word channel for a pore that
has a gate that determines how long it will be in the fully open
49
50 Bioenergetics | Membrane Transport, General Concepts
Figure 1 Illustration of phospholipid bilayer with peripheral proteins
adhering to the surfaces and integral proteins spanning the thickness of
the membrane. One integral protein is portrayed as a channel. The
charged head groups of the phospholipids are represented as circles
and the lipophilic fatty tail groups as the wavy lines forming the core
of the bilayer.
state and how long it will be closed (the analogy being a pipe
with shutter).
In general, then, channels have gates that determine the
probability that they will be in the open state at any time
(open-time probability) and how long they will stay open
(mean open time). The properties of these gates may be influ-
enced by the electrical potential difference across the mem-
brane (voltage-gated channels), the binding of one or more
ligands (ligand-gated channels) or both. In addition, they
possess ‘filters’ that confer selectivity on the channel; the struc-
tural characteristics of ion channels that result in a high prefer-
ence for one ion over the other have recently been unraveled
for potassium channels.
Movement of an ion through an open channel obeys a form
of Ohm’s law for current flow caused by a conductance driven
by an electrochemical potential difference. Thus,
ii ¼ gi ðVm  Ei Þ
where ii is the rate of flow of the ion through a single open
channel given in electrical terms of amperes (this is analogous
to Ji) and gi the conductance of the channel (analogous to Pi).
Vm is the electrical potential difference across the membrane
and Ei the Nernst equilibrium potential for the ion so that the
difference (Vm  Ei) is the displacement of the ion from equi-
librium in electrical terms, and is thus the driving force for
flow. More than one million ions may traverse a single channel
per second so that single channel currents may be readily
recorded using a variety of techniques. The ionic current through
an ensemble of such channels is Ii ¼ iiNipo, where Ni is the total
number of channels and po the open probability.
Carrier-Mediated Transport
Carrier-mediated transport differs from diffusion through lipid
phase, pores, or channels in that after entering the integral
protein the transported solute(s) bind to a specific site(s) on
this protein which then undergoes some translocation that
exposes and/or releases them to the other side. Unlike pores
or channels, carriers are not open to both sides of the
membrane simultaneously. Because conformational changes
are necessary for carriers to function, the number of molecules
transported per second is orders of magnitude less than pores.
In this sense, carriers may be viewed as enzymes that do not
chemically alter the transported species (substrate)
but, instead, catalyze a change in their location. For this
reason, the terms permeases and translocases are used in
some instances as synonymous with carriers. Indeed, one
characteristic of carrier-mediated transport is that it displays
Michaelis–Menten saturation kinetics, marked by a maximum
transport velocity (Jm) and a solute concentration needed to
achieve a half-maximal transport velocity (Kt), and often obeys
the simple relation:
JS ¼ f½SJm =Km þ ½Sg
where JS is the rate of transport and [S] the concentration of the
transported solute. (Note: this relation describes the initial rate
of transport when there is solute present on one side of the
membrane only.)
Facilitated Diffusion
The earliest recognized and simplest form of carrier-mediated
transport is facilitated diffusion, often called facilitated trans-
port, in which an otherwise impermeant solute binds to a site on
an integral protein (carrier) from one side of the membrane and
then undergoes a translocation that provides the solute access to
the other side. The classic example of facilitated diffusion is
glucose transport across the membranes of cells such as erythro-
cytes, muscle, and adipocytes. The carriers that mediate this
transport have been cloned and sequenced and fall into a
group of proteins that have 12 membrane-spanning segments
called glucose transporter (GLUT). Urea is transported across the
membranes of many cells by a facilitated transporter called UT.
It must be emphasized that because these carriers are
not directly or indirectly coupled to a supply of energy, they
cannot perform osmotic work, that is, they cannot transport a
neutral solute against a concentration difference (e.g., from
lower to higher concentration) or a charged solute against a
combined electrochemical potential difference. Thus, like dif-
fusion, facilitated diffusion carriers bring about equilibration;
transport ceases when intrinsic thermodynamic driving forces
are abolished.
Active Transport
Active transport is the term reserved for transport processes that
result in the movement of a solute uphill or against its natural
direction. For the case of a neutral solute (at constant tempera-
ture and pressure), this resolves into movement against a con-
centration difference; for a charged solute, it is movement
against the combination of concentration and electrical poten-
tial differences. This is work (e.g., charging a battery) and it
therefore requires the investment of energy.
There are two groups of carrier-mediated active transport
processes: those where the coupling to energy is direct and
those where the coupling to energy is indirect.

Primary Active Transport
Primary active transport processes are capable of coupling
energy directly to the uphill movement of the transported
species. By far the most abundant, and well-understood, pri-
mary active transporters are the retinylidene proteins or, more
commonly called, rhodopsins, capable of coupling light energy
to ion transport. Bacteriorhodopsins found in Archaea, Circhaea,
and some eukaryotic and prokaryotic cells pump protons out of
these cells, thereby establishing a ‘proton-motive force’ across
the membrane. Holophilic bacteria possess a form referred
to as halorhodopsin that pumps Cl into cells. These trans-
porters have been studied extensively using high-resolution
crystallography and all possess seven membrane-spanning
segments attached to a chromophore.
In higher animals, all primary active transporters are ATPases,
that derive the energy for moving the transported solute against
a thermodynamic driving force (i.e., uphill) from adenosine
triphosphate (ATP) hydrolysis. The most prevalent is the Na–K
pump found in virtually all cells from higher animals and
responsible for pumping three Naþ ions out of the cell and
two Kþ ions into the cell for every ATP hydrolyzed. This pump
is responsible for the fact that these cells have a lower intracellu-
lar Naþ concentration and higher intracellular Kþ concentration
than the concentrations of these ions in the surrounding extra-
cellular fluid. As is discussed below, the extrusion of Naþ from
the cell establishes a ‘natrio-motive’ force across the membrane
analogous to the proton-motive force established by light-driven
proton pumps in lower life forms. The detailed mechanism of
action of the Na–K pump is not well established except for the
fact that it is a member of a superfamily of ATPases referred to as
E1–E2 ATPases or P-type ATPases, because the operation of
the pump involves cycling between two configurations of the
protein driven by phosphorylation and dephosphorylation
reactions.
Other ATPases that perform primary active transport
include the Ca2þ ATPase found in muscle and responsible for
regulation of the Ca2þ activity of the cytoplasm, the Hþ–Kþ
ATPase of gastric parietal cells responsible for secreting protons
into the gastric juice in response to appropriate stimuli, and the
Hþ ATPase that is responsible for acidifying intracellular orga-
nelles such as lysosomes and endosomes.
Secondary Active Transport
Secondary active transport processes bring about the uphill
transport of one or more solutes but do not derive the neces-
sary energy from direct coupling to a source of metabolic
energy. Instead, these transport processes are energized by
coupling those movements to the downhill movement of
another solute.
Co-Transport (Symport)
The uphill or secondary active transport of a large number of
solutes into cells of higher animals is coupled to the downhill
Bioenergetics | Membrane Transport, General Concepts 51
movement of Naþ. Thus, the carrier protein binds both the
transported solute and Naþ from the extracellular solution.
Inasmuch as the Naþ concentration in the intracellular
solution is lower than that in the extracellular solution,
because of the action of the Naþ–Kþ pump as discussed,
this coupling permits the downhill movement of Naþ and
provides the energy for the uphill movement of the coupled
solute. In essence, the energy invested into the Naþ–Kþ pump
by the hydrolysis of ATP has set up a Naþ-gradient
or natrio-motive force across the membrane that can be
deployed to energize the secondary active transport of solutes
whose translocation across the membrane is coupled to that
of Naþ.
In many lower forms of life, secondary active co-transport is
energized by the Hþ gradient or proton-motive force across the
membrane established and maintained by light-driven primary
active extrusion of protons, as discussed above.
Counter-Transport (Antiport)
Coupling to the downhill movement of Naþ into cells can also
serve to energize the uphill or secondary active transport of
solutes out of cells. Important examples of counter-transporters
are the Naþ–Hþ exchanger responsible for extruding Hþ from
cells and the regulation of cell pH and the Naþ–Ca2þ
exchanger responsible for extruding Ca2þ from many cells.
Naþ-coupled co- and counter-transport processes are very
diverse and are beautiful examples of bioenergetic economy
where a single primary active transport process directly coupled
to the hydrolysis of ATP can establish a transmembrane ion
(Naþ) gradient that can, in turn, be utilized to energize a wide
variety of secondary active transport processes.
See also: Bioenergetics: ER/SR Calcium Pump: Function; ER/SR
Calcium Pump: Structure; Membrane Transporters: Na+/Ca2+
Exchangers; Plasma-Membrane Calcium Pump: Structure and
Function; P-Type Pumps: Copper Pump; P-Type Pumps: H+/K+ Pump;
P-Type Pumps: Na+,K+-ATPase; P-Type Pumps: Plasma-Membrane H+
Pumps.
Further Reading
Bretscher MS (1985) The molecules of the cell membrane. Scientific American 253(4):
100–108.
Doyle DA, Cabral JM, Pfuetzner RA, et al. (1998) The structure of the potassium
channel: Molecular basis of Kþ conductance and selectivity. Science
280: 69–77.
Hille B, Armstrong CM, and MacKinnon R (1999) Ion channels: From idea to reality.
Nature Medicine 5: 1105–1109.
Schultz SG (1982) Basic Principles of Membrane Transport. Cambridge: Cambridge
University Press.
Schultz SG (2003) Membrane transport. In: Johnson LR (ed.) Essential Medical
Physiology, 3rd edn., pp. 37–70. San Diego, CA: Academic Press.
Spudich JL, Yang C-S, Jung K-H, and Spudich EN (2000) Retinylidene proteins:
Structures and functions from Archaea to humans. Annual Review of Cell and
Developmental Biology 16: 365–392.