Unit 2-plasma membrane and membrane transport

Plasma membrane and Membrane transport,
By, K. P. Komal, Asst. Prof. GSC, CTA.
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Lecture notes in Cellular Biochemistry
Topic: Plasma membrane and Membrane transport
By,
Mrs. K. P. Komal
Assistant professor in Biochemistry
Government Science College, Chitradurga
Karnataka. 577501

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Plasma Membrane
The biological membrane, which is present in both eukaryotic and prokaryotic cell. It is
also called as cell membrane as it is works as a barrier between the inner and outer surface
of a cell. In animal cells, the plasma membrane is present in the outer most layer of the cell
and in plant cell it is present just beneath the cell wall.
Structure of Plasma Membrane
Plasma Membrane Definition
Plasma membrane can be defined as a biological membrane or an outer membrane of a
cell, which is composed of two layers of phospholipids and embedded with proteins. It is a
thin semi permeable membrane layer, which surrounds the cytoplasm and other
constituents of the cell.
Functions of Plasma Membrane
1. It separates the contents of the cell from its outside environment and it regulates
what enters and exits the cell.
2. Plasma membrane plays a vital role in protecting the integrity of the interior of the
cell by allowing only selected substances into the cell and keeping other substances
out.
3. It also serves as a base of attachment for the cytoskeleton in some organisms and
the cell wall in others. Thus the cell membrane supports the cell and helps in
maintaining the shape of the cell.
4. The cell membrane is primarily composed of proteins and lipids. While lipids help to
give membranes their flexibility and proteins monitor and maintain the cell's
chemical climate and assist in the transfer of molecules across the membrane.
5. The lipid bilayer is semi-permeable, which allows only selected molecules to diffuse
across the membrane.

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Characteristics of Plasma Membrane
1. The plasma membrane (cell membrane) is made of two layers of phospholipids.
2. The plasma membrane has many proteins embedded in it.
3. The plasma membrane regulates the entry and exit of the cell. Many molecules cross
the cell membrane by diffusion and osmosis.
4. The fundamental structure of the membrane is phospholipidbilay and it forms a
stable barrier between two aqueous compartments.
5. The proteins present in the plasma membrane, act as pumps, channels, receptors,
enzymes or structural components.
Plasma Membrane Structure
1. It is the boundary, which separates the living cell from their non-living surroundings
2. It is the phospholipids bilayer.
3. Plasma membrane is an amphipathic, which contains both hydrophilic heads and
hydrophobic tails.
4. It is a fluid mosaic of lipids, proteins and carbohydrate.
5. It is lipid bilayer, which contains -two layers of phospholipids, phosphate head is
polar (water loving), fatty acid tails non-polar (water fearing) and the proteins
embedded in membrane.
Components of Plasma Membrane
The main components of plasma membrane include:
1. Proteins like glycoprotein, which are used for cell recognition and act as receptors
and antigens.
2. Proteins like glycolipids are attached to phospholipids along with the sugar chains.
3. Lipids with short chain of carbohydrates are attached on the extracellular side of the
membrane.
4. Phospholipid Bilayer - which are made up of phosphates and lipids. They create a
partially permeable membrane, which allows only certain substances to diffuse
through the membrane.
5. Cholesterol – it maintains the fluidity of cell surface membrane.
Proteins in Plasma Membrane
In plasma membrane, a protein helps in providing the support and shape to the cell. There
are three types of proteins in plasma membrane, which includes:
1. Cell membrane receptor proteins- It helps in communication of cell with their
external environment with the help of hormones: neurotransmitters and other
signalling molecules.
2. Transport proteins: It helps in transporting molecules across cell membranes
through facilitated diffusion. For example: globular proteins.
3. Glycoprotein- It helps in cell to cell communications and molecule transport across
the membrane.

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Fluid mosaic model
• The fluid mosaic model explains various observations regarding the structure of
functional cell membranes. The model, which was devised by S J Singer and G L
Nicolson in 1972, describes the cell membrane as a two-dimensional liquid in which
that restrict the lateral diffusion of membrane components. Such domains are
defined by the existence of regions within the membrane with special lipid and
protein composition that promote the formation of lipid rafts or protein and
glycoprotein complexes.
• Another way to define membrane domains is the association of the lipid membrane
with the cytoskeleton filaments and the extracellular matrix through membrane
proteins.
• The current model describes important features relevant to many cellular
processes, including: cell-cell signaling, apoptosis, cell division, membrane budding,
and cell fusion.
Membrane transport:
• In cellular biology, membrane transport refers to the collection of mechanisms
that regulate the passage of solutes such as ions and small molecules through
biological membranes, which are lipid bilayers that contain proteins embedded in
them.
• The regulation of passage through the membrane is due to selective membrane
permeability - a characteristic of biological membranes which allows them to
separate substances of distinct chemical nature. In other words, they can be
permeable to certain substances but not to others.
• The movements of most solutes through the membrane are mediated by membrane
transport proteins which are specialized to varying degrees in the transport of
specific molecules.

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Diagram of a cell membrane
1. phospholipid 2. cholesterol 3. glycolipid 4. sugar 5. polytopic protein (transmembrane protein) 6. monotopic protein
(here, a glycoprotein) 7. monotopic protein anchored by a phospholipid 8. peripheral monotopic protein (here, a
glycoprotein.)
The nature of biological membranes, especially that of its lipids, is amphiphilic, as they
form bilayers that contain, an internal hydrophobic layer and an external hydrophilic layer.
This structure makes transport possible by simple or passive diffusion, which consists of
the diffusion of substances through the membrane without expending metabolic energy
and without the aid of transport proteins. If the transported substance has a net electrical
charge, it will move not only in response to a concentration gradient, but also to an
electrochemical gradient due to the membrane potential.
Relative permeability of a phospholipid bilayer to various substances
Type of substance Examples Behaviour
Gases CO2, N2, O2 Permeable
Small uncharged polar molecules Urea, water, ethanol
Permeable, totally or
partially
Large uncharged polar molecules glucose, fructose Not permeable
Ions K+, Na+, Cl−, HCO3− Not permeable
Charged polar molecules
ATP, amino acids,
glucose-6-phosphate
Not permeable
As few molecules are able to diffuse through a lipid membrane the majority of the transport
processes involve transport proteins. These transmembrane proteins possess a large
number of alpha helices immersed in the lipid matrix. In bacteria these proteins are
present in the beta lamina form. This structure probably involves a conduit through
hydrophilic protein environments that cause a disruption in the highly hydrophobic
medium formed by the lipids. These proteins can be involved in transport in a number of

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ways: they act as pumps driven by ATP, that is, by metabolic energy, or as channels of
facilitated diffusion.
Transport types
Passive transport is a movement of biochemicals and other atomic or molecular
substances across cell membranes without need of energy input. Unlike active transport,
it does not require an input of cellular energy because it is instead driven by the tendency
of the system to grow in entropy. The rate of passive transport depends on
the permeability of the cell membrane, which, in turn, depends on the organization and
characteristics of the membrane lipids and proteins. The four main kinds of passive
transport are
• simple diffusion,
• facilitated diffusion,
• filtration
• and osmosis.
Simple diffusion
• Diffusion is the net movement of material from an area of high concentration to an
area with lower concentration.
• The difference of concentration between the two areas is often termed as
the concentration gradient, and diffusion will continue until this gradient has been
eliminated.
• Since diffusion moves materials from an area of higher concentration to an area of
lower concentration, it is described as moving solutes "down the concentration
gradient" (compared with active transport, which often moves material from area of
low concentration to area of higher concentration, and therefore referred to as
moving the material "against the concentration gradient").
• Simple diffusion and osmosis are in some ways similar. Simple diffusion is the
passive movement of solute from a high concentration to a lower concentration
until the concentration of the solute is uniform throughout and reaches equilibrium.
Osmosis is much like simple diffusion but it specifically describes the movement of
water (not the solute) across a selectively permeable membrane until there is an
equal concentration of water and solute on both sides of the membrane.
• Simple diffusion and osmosis are both forms of passive transport and require none
of the cell's ATP energy.
• Example: transport of gases across the membrane i.e oxygen, carbon dioxide etc.
Facilitated diffusion
• Facilitated diffusion, also called carrier-mediated osmosis, is the movement of
molecules across the cell membrane via special transport proteins that are
embedded within the cellular membrane.

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• Large, insoluble molecules, such as glucose, vesicles and proteins require a carrier
molecule to move through the plasma membrane. Therefore, it will bind with its
specific carrier proteins, and the complex will then be bonded to a receptor site and
moved through the cellular membrane.
• Facilitated diffusion is a passive process: The solutes move down the concentration
gradient and don't use extra cellular energy to move.
• Channel proteins are another type of facilitated diffusion that allow the selective
transport of one type of hydrophilic molecule across the cell membrane.
• Aquaporins are channel proteins that allow the passage of water across the cell
membrane.
• Facilitated diffusion may be achieved as a consequence of charge gradients in
addition to concentration gradients. Plant cells create an unequal distribution of
charge across their plasma membrane by actively taking up or excluding ions. Active
transport of protons by H+ ATPases alters membrane potential allowing for
facilitated passive transport of particular ions such as Potassium down their charge
gradient through high affinity transporters and channels.
Uniporter:
• A uniporter is an integral membrane protein that is involved in facilitated diffusion.
They can be either ion channels or carrier proteins.
• Uniporter carrier proteins work by binding to one molecule of substrate at a time
and transporting it with its concentration gradient. Uniporter channels open in
response to a stimulus and allow the free flow of specific molecules. Both kinds of
uniporters rely on passive transport, as they do not directly require cellular energy
to function.
• There are several ways in which the opening of uniporter channels may be
regulated:
1. Voltage - Regulated by the difference in voltage across the membrane
2. Stress - Regulated by physical pressure on the transporter (as in the cochlea
of the ear)
3. Ligand - Regulated by the binding of a ligand to either the intracellular or
extracellular side of the cell
• Uniporters are involved in many biological processes, including action potentials in
neurons.
• Voltage-gated sodium channels are involved in the propagation of a nerve impulse
across the neuron. During transmission of the signal from one neuron to the
next, calcium is transported into the pre-synaptic neuron by voltage-gated calcium
channels. Potassium leak channels, also regulated by voltage, then help to restore
the resting membrane potential after impulse transmission.
Symporter:

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• A symporter is an integral membrane protein that is involved in the transport of
many differing types of molecules across the cell membrane.
• The symporter works in the plasma membrane and molecules are transported
across the cell membrane at the same time, and is, therefore, a type of cotransporter.
• The transporter is called a symporter, because the molecules will travel in the same
direction in relation to each other.
• This is in contrast to the antiport transporter. Typically, the ion(s) will move down
the electrochemical gradient, allowing the other molecule(s) to move against the
concentration gradient.
• The movement of the ion(s) across the membrane is facilitated diffusion, and is
coupled with the active transport of the molecule(s).
Examples
• SGLT1 in the intestinal epithelium transports sodium ions (Na+) and glucose across
luminal membrane of the epithelial cells so that it can be absorbed into the
bloodstream. This is the basis of oral rehydration therapy. If this symporter did not
exist, individual sodium channels and glucose uniporters would not be able to
transfer glucose against the concentration gradient and into the bloodstream.
• Na+/K+/2Cl− symporter in the loop of Henle in the renal tubules of
the kidney transports 4 molecules of 3 different types; a sodium ion (Na+), a
potassium ion (K+) and two chloride ions (2Cl−). Loop diuretics such
as furosemide (Lasix) act on this protein.
Antiporter:
• An antiporter (also called exchanger or counter-transporter) is a cotransporter
and integral membrane protein involved in secondary active transport of two or
more different molecules or ions across a phospholipid membrane such as
the plasma membrane in opposite directions. Ex. Na+/H+ antiporters
• In secondary active transport, one species of solute moves along its electrochemical
gradient, allowing a different species to move against its own electrochemical
gradient. This movement is in contrast to primary active transport, in which all
solutes are moved against their concentration gradients, fueled by ATP.
Transport may involve one or more of each type of solute. For example,
the Na+/Ca2+ exchanger, used by many cells to remove cytoplasmic calcium, exchanges one
calcium ion for three sodium ions.

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Facilitated Diffusion
Active transport
• Active transport is the movement of molecules across a cell membrane from a
region of their lower concentration to a region of their higher concentration in the
direction against some gradient or other obstructing factor (often a concentration
gradient).
• Unlike passive transport, which uses the kinetic energy and natural entropy of
molecules moving down a gradient, active transport uses cellular energy to move
them against a gradient, polar repulsion, or other resistance.
• Active transport is usually associated with accumulating high concentrations of
molecules that the cell needs, such as ions, glucose and amino acids.
• If the process uses chemical energy, such as from adenosine triphosphate (ATP), it is
termed primary active transport. Secondary active transport involves the use of
an electrochemical gradient. Examples of active transport include the uptake of
glucose in the intestines in humans and the uptake of mineral ions into root
hair cells of plants.
Primary Active Transport
• Primary active transport utilizes energy in form of ATP to transport molecules
across a membrane against their concentration gradient. Therefore, all groups of
ATP-powered pumps contain one or more binding sites for ATP, which are always
present on the cytosolic face of the membrane.
Based on the transport mechanism as well as genetic and structural homology, there are
considered four classes of ATP-dependent ion pumps:
o P-class pumps: Na+/K+ pump, calcium pump, proton pump
o F-class pumps: mitochondrial ATP synthase, chloroplast ATP synthase
o V-class pump: vacuolar ATPase
o ABC superfamily/ ABC (ATP binding cassette) transporter: MDR, CFTR, etc.
The P-, F- and V-classes only transports ions, while the ABC superfamily also transports
small molecules.
The energy expended by cells to maintain the concentration gradients of some ions across
the plasma and intracellular membranes is considerable:

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o In kidney cells, up to 25 % of the ATP produced by the cell is used for ion
transport;
o In electrically active nerve cells, 60 -70 % of the cells’ energy requirement
may be devoted to pumping Na+ out of the cell and K+ into the cell.
Example: Na+/K+ pump
P-type ATPase
• The P-type ATPases, also known as E1-E2 ATPases, are a large group of
evolutionarily related ion and lipid pumps that are found inbacteria, archaea,
and eukaryotes.
• P-type ATPases fall under the P-type ATPase (P-ATPase) Superfamily which, as of
early 2016, includes 20 different protein families. P-type ATPases are α-helical
bundle primary transporters named based upon their ability to catalyze auto- (or
self-) phosphorylation of a key conserved aspartate residue within the pump and
their energy source, adensosine triphosphate (ATP).
• In addition, they all appear to interconvert between at least two different
conformations, denoted by E1 and E2.
• Most members of this transporter superfamily catalyze cation uptake and/or efflux,
however one subfamily is involved in flipping phospholipids to maintain the
asymmetric nature of the biomembrane.
• Prominent examples of P-type ATPases are the sodium-potassium pump (Na+/K+-
ATPase), the plasma membrane proton pump (H+-ATPase), the proton-potassium
pump (H+/K+-ATPase), and the calcium pump (Ca2+-ATPase).
Na+/K+ pump:
• Na+/K+-ATPase (sodium-potassium adenosine triphosphatase, also known as
the Na+/K+ pump or sodium-potassium pump) is an enzyme (EC 3.6.3.9) (an
electrogenic transmembrane ATPase) found in the plasma membrane of
all animal cells.
• The Na+/K+-ATPase enzyme is a solute pump that pumps sodium out of cells while
pumping potassium into cells, both against their concentration gradients.
• This pumping is active (i.e. it uses energy from ATP) and is important for cell
physiology. An example application is nerve conduction.
• It has antiporter-like activity but is not actually an antiporter since both molecules
are moving against their concentration gradient.
Mechanism:
• The pump, after binding ATP, binds 3 intracellular Na+ ions.
• ATP is hydrolyzed, leading to phosphorylation of the pump at a highly
conserved aspartate residue and subsequent release of ADP.

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• A conformational change in the pump exposes the Na+ ions to the outside. The
phosphorylated form of the pump has a low affinity for Na+ ions, so they are
released.
• The pump binds 2 extracellular K+ ions. This causes the dephosphorylation of the
pump, reverting it to its previous conformational state, transporting the K+
ions into the cell.
• The unphosphorylated form of the pump has a higher affinity for Na+ ions
than K+ ions, so the two bound K+ ions are released. ATP binds, and the process
starts again.
Functions
• The Na+/K+-ATPase helps maintain resting potential, effect transport, and regulate
cellular volume.
• It also functions as a signal transducer/integrator to regulate MAPK pathway, ROS,
as well as intracellular calcium. In most animal cells, the Na+/K+
-ATPase is responsible for about 1/5 of the cell's energy expenditure. For neurons,
the Na+/K+-ATPase can be responsible for up to 2/3 of the cell's energy
expenditure.
F-ATPase
• F-ATPase, also known as F-Type ATPase (also called ATP synthase), is
an ATPase found in bacterial plasma membranes, in mitochondrial inner
membranes (in oxidative phosphorylation, where it is known as Complex V), and
in chloroplast thylakoid membranes.
• It uses a proton gradient to drive ATP synthesis by allowing the passive flux of
protons across the membrane down their electrochemical gradient and using the
energy released by the transport reaction to release newly formed ATP from the
active site of F-ATPase. In some bacteria, sodium ions may be used instead.
F-ATPase consists of two domains:
the Fo domain, which is integral in the membrane
the F1, which is peripheral (on the side of the membrane that the protons are
moving into).
Structure
• Fo-F1 particles are mainly formed of polypeptides.
• The F1-particle contains 5 types of polypeptides, with the composition-ratio--
3α:3β:1δ:1γ:1ε.
• The Fo has the 1a:2b:12c composition. Together they form a rotary motor. As the
protons bind to the subunits of the Fo domains, they cause parts of it to rotate. This
rotation is propagated by a 'camshaft' to the F1 domain. ADP and Pi (inorganic
phosphate) bind spontaneously to the three β subunits of the F1 domain, so that
every time it goes through a 120° rotation ATP is released (rotational catalysis).

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• The o in the Fo stands for oligomycin, because oligomycin is able to inhibit its
function.
V-ATPase
• Vacuolar-type H+-ATPase (V-ATPase) is a highly conserved evolutionarily
ancient enzyme with remarkably diverse functions in eukaryotic organisms.
• V-ATPases acidify a wide array of intracellular organelles and pump protons across
the plasma membranes of numerous cell types.
• V-ATPases couple the energy of ATP hydrolysis to proton transport across
intracellular and plasma membranes of eukaryotic cells.
• It is generally seen as the polar opposite of ATP Synthase because ATP Synthase is a
proton channel that uses the energy from a proton gradient to produce ATP.
• V-ATPase however, is a proton pump that uses the energy from ATP hydrolysis to
produce a proton gradient.
Roles played by V-ATPases
• V-ATPases are found within the membranes of many organelles, such
as endosomes, lysosomes, and secretory vesicles, where they play a variety of roles
crucial for the function of these organelles.
• For example, the proton gradient across the yeast vacuolar membrane generated by
V-ATPases drives calcium uptake into the vacuole through an H+/Ca2+
antiporter system.
• In synaptic transmission in neuronal cells, V-ATPase acidifies synaptic vesicles.
• Norepinephrine enters vesicles by V-ATPase.
• V-ATPases are also found in the plasma membranes of a wide variety of cells such
as intercalated cells of the kidney, osteoclasts (bone resorbing cells),
macrophages, neutrophils, sperm, midgut cells of insects, and certain tumor cells.

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• Plasma membrane V-ATPases are involved in processes such
as pH homeostasis, coupled transport, and tumor metastasis.
• V-ATPases in the acrosomal membrane of sperm acidify the acrosome. This
acidification activates proteases required to drill through the plasma membrane of
the egg.
• V-ATPases in the osteoclast plasma membrane pump protons onto the bone surface,
which is necessary for bone resorption.
• In the intercalated cells of the kidney, V-ATPases pump protons into the urine,
allowing for bicarbonate reabsorption into the blood.
ABC transporter: (ATP-binding cassette transporter)
• ATP-binding cassette transporters (ABC transporters) are members of a
transport system super family that is one of the largest and is possibly one of the
oldest families with representatives in all extant phyla from prokaryotes to humans.
• ABC transporters often consist of multiple subunits, one or two of which are
transmembrane proteins and one or two of which are membrane-
associated ATPases.
• The ATPase subunits that utilize the energy of adenosine triphosphate (ATP)
binding and hydrolysis to energize the translocation of various substrates across
membranes, either for uptake or for export of the substrate.
• ABC transporters are considered to be with the ABC superfamily based on the
sequence and organization of their ATP-binding cassette (ABC) domains, even

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though the integral membrane proteins may have evolved independently several
times, and thus comprise different protein families.
• The integral membrane proteins of ABC exporters appear to have evolved
independently at least three times.
• ABC1 exporters evolved by intragenic triplication of a 2 TMS precursor to give 6
TMS proteins. ABC2 exporters evolved by intragenic duplication of a 3 TMS
precursor, and ABC3 exporters evolved from a 4 TMS precursor which duplicated
either extragenicly to give two 4 TMS proteins, both required for transport function,
or intragenicly to give 8 or 10 TMS proteins.
• ABC uptake porters take up a large variety of nutrients, biosynthetic precursors,
trace metals and vitamins, while exporters transport lipids, sterols, drugs, and a
large variety of primary and secondary metabolites.
• Some of these exporters in humans are involved in tumor resistance, cystic
fibrosis and a range of other inherited human diseases. High level expression of the
genes encoding some of these exporters in both prokaryotic and eukaryotic
organisms (including human) result in the development of resistance to multiple
drugs such as antibiotics and anti-cancer agents.
• Forty eight ABC genes have been reported in humans. Among these, many have been
of these have been characterized and shown to be causally related to diseases
present in humans such as cystic fibrosis, adrenoleukodystrophy, Stargadt’s disease,
drug-resistant tumors, Dubin-Johnson syndrome, Byler’s disease, progressive
familiar intrahepatic cholestasis, X-linked sideroblastic anemia, ataxia, and
persistent and hyperinsulimenic hypoglycemia.
• ABC transporters are also involved in multiple drug resistance, and this is how
some of them were first identified. When the ABC transport proteins are over
expressed in cancer cells, they can export anticancer drugs and render tumors
resistant.

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Secondary Active Transport
• Secondary active transport is transport of molecules across the cell membrane
utilizing energy in other forms than ATP. This energy comes from the
electrochemical gradient created by pumping ions out of the cell. This Co-Transport
can be either via antiport or symport.
The formation of the electrochemical gradient, which enables the co-transport, is made by
the primary active transport of Na+. Na+ is actively transported out of the cell, creating a
much higher concentration extracellularly than intracellularly. This gradient becomes
energy as the excess Sodium is constantly trying to diffuse to the interior. This mechanism
provides the energy needed for the co-transport of other ions and substances.
Mechanism
• The formation of the electrochemical gradient which enables the co-transport is
made by the primary active transport of Na+.
• Na+ is actively transport out of the cell creating a much higher concentration
extracellular than intracellular.
• This gradient becomes energy as the excess Sodium is constantly trying to diffuse to
the interior.
Antiport
Antiport or Counter-transport means that 2 different molecules or ions are being
transported at the same time but opposite directions. One of the species is allowed to flow

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from high concentration to a lower concentration (often Sodium) while the other species is
transported simultaneously to the other side.
Examples:
• Na+-Ca2+ counter-transport where Na+ binds to the transport carrier protein on
its exterior side, and Ca2+ bound to the same protein on the membranes interior
side. Once both are bound, a conformational change occurs which releases
energy and the sodium ion is transported to the interior and calcium to the
exterior. This transporter is situated on almost all cell membranes.
• Na+-H+ counter-transport. The mechanism is the same as the previous example.
However the advantage of this transporter is clearly seen in the proximal
tubules of the kidneys. The mechanism for concentrating H+ is not nearly as
powerful as Primary active transport, however it can transport extremely large
numbers and thus making it a key in H+ homeostasis in the body.
Symport
Symport or "Co-transport" means that a molecule is allowed to be transported from high to
low concentration region while moving another molecule with it from low to high
concentration. It in fact is pulling the other molecule with it into the cell.
Examples:
• Sodium-Glucose co-transport mechanism. On its exterior side the transport
protein has 2 binding sites, one for sodium and one for glucose. When both of
these bind to the protein there is a conformational change allowing the
electrochemical gradient to provide the energy needed to transport both of
these molecules into the cell.
• Sodium-Amino acid co-transport occurs in the same manner as for glucose,
except that uses a different set of transport proteins, however its mechanism is
the same.
These transporters occur especially through the epithelial cells of the intestinal tract and
the renal tubules of the kidneys to enable absorption of these substances into blood.
Endocytosis:
• Endocytosis is a form of active transport in which a cell transports molecules (such
as proteins) into the cell (endo- + cytosis) by engulfing them in an energy-using
process.
• Endocytosis and its counterpart, exocytosis, are used by all cells because
most chemical substances important to them are large polar molecules that cannot
pass through the hydrophobic plasma or cell membrane by passive means.
Endocytosis includes pinocytosis (cell drinking) and phagocytosis (cell eating).
Endocytosis pathways
Endocytosis pathways can be subdivided into four categories: namely,
receptor-mediated endocytosis,

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caveolae,
macropinocytosis, and
phagocytosis.
Clathrin-mediated endocytosis:
It is mediated by small (approx. 100 nm in diameter) vesicles that have a
morphologically characteristic coat made up of a complex of proteins that are
mainly associated with the cytosolic protein clathrin.
Clathrin-coated vesicles (CCVs) are found in virtually all cells and form domains of
the plasma membrane termed clathrin-coated pits.
Coated pits can concentrate large extracellular molecules that have
different receptors responsible for the receptor-mediated endocytosis of ligands,
e.g. low density lipoprotein, transferrin, growth factors, antibodies and many others.
Function
The function of receptor-mediated endocytosis is diverse.
It is widely used for the specific uptake of certain substances required by the cell
(examples include LDL via the LDL receptor or iron via transferrin).
The role of receptor-mediated endocytosis is also well recognized in the
downregulation of transmembrane signal transduction. The activated receptor
becomes internalised and is transported to late endosomes and lysosomes for
degradation.
However, receptor-mediated endocytosis is also actively implicated in transducing
signals from the cell periphery to the nucleus. This became apparent when it was
found that the association and formation of specific signaling complexes is required
for the effective signaling of hormones (e.g. EGF). Additionally it has been proposed
that the directed transport of active signaling complexes to the nucleus might be
required to enable signaling as random diffusion is too slow and mechanisms
permanently down regulating incoming signals are strong enough to shut down
signaling completely without additional signal-transducing mechanisms
Caveolae:
Caveolae are the most common reported non-clathrin-coated plasma membrane
buds, which exist on the surface of many, but not all cell types.
They consist of the cholesterol-binding protein caveolin (Vip21) with a bilayer
enriched in cholesterol and glycolipids.
Caveolae are small (approx. 50 nm in diameter) flask-shape pits in the membrane
that resemble the shape of a cave (hence the name caveolae).
They can constitute up to a third of the plasma membrane area of the cells of some
tissues, being especially abundant insmooth muscle, type
I pneumocytes, fibroblasts, adipocytes, and endothelial cells.
Uptake of extracellular molecules is also believed to be specifically mediated via
receptors in caveolae.

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Other roles of caveolae
• Caveolae can be used for entry to the cell by some pathogens and so they avoid
degradation in lysosomes. However, some bacteria do not use typical caveolae
but only caveolin-rich areas of the plasma membrane. The pathogens exploiting
this endocytic pathway include viruses such as SV40 and polyoma virus and
bacteria such as some strains of Escherichia coli, Pseudomonas
aeruginosa and Porphyromonas gingivalis.
• Caveolae have a role in the cell signaling, too. Caveolins associate with some
signaling molecules (e.g. eNOS) through their scaffolding domain and so they can
regulate their signaling. Caveolae are also involved in regulation of channels and
in calcium signaling.
• Caveolae also participate in lipid regulation. High levels of caveolin Cav1 are
expressed in adipocytes. Caveolin associates with cholesterol, fatty acids and
lipid droplets and is involved in its regulation.
• Caveolae can also serve as mechanosensors in various cell types. In endothelial
cells, caveolae are involved in flow sensation. Chronic exposure to the flow
stimulus leads to increased levels of caveolin Cav1 in plasma membrane, its
phosphorylation, activation of eNOS signaling enzyme and to remodeling of
blood vessels. In smooth-muscle cells, caveolin Cav1 has a role in stretch sensing
which triggers cell-cycle progression
Macropinocytosis:
which usually occurs from highly ruffled regions of the plasma membrane, is the
invagination of the cell membrane to form a pocket, which then pinches off into the
cell to form a vesicle (0.5–5 µm in diameter) filled with a large volume of
extracellular fluid and molecules within it (equivalent to ~100 CCVs).
The filling of the pocket occurs in a non-specific manner. The vesicle then travels
into the cytosol and fuses with other vesicles such as endosomes and lysosomes.
In cellular biology, pinocytosis, otherwise known as cell drinking, fluid
endocytosis, and bulk-phase pinocytosis, is a mode of endocytosis in which small
particles are brought into the cell, forming an invagination, and then suspended
within small vesicles.
These pinocytotic vesicles subsequently fuse with lysosomes to hydrolyze (break
down) the particles. This process requires a lot of energy in the form of adenosine
triphosphate (ATP), the chemical compound mostly used as energy in the majority
of animal cells.
Pinocytosis is used primarily for the absorption of extracellular fluids (ECF). In
contrast to phagocytosis, it generates very small amounts of ATP from the wastes of
alternative substances such as lipids (fat).

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Unlike receptor-mediated endocytosis, pinocytosis is nonspecific in the substances
that it transports. The cell takes in surrounding fluids, including all solutes present.
Pinocytosis also works as phagocytosis; the only difference is that phagocytosis is
specific in the substances it transports. Phagocytosis engulfs whole particles, which
are later broken down by enzymes, such as cathepsins, and absorbed into the cells.
Pinocytosis, on the other hand, is when the cell engulfs already-dissolved or broken-
down food.
Pinocytosis is non-specific and non-absorptive. Molecule-specific endocytosis is
called receptor-mediated endocytosis.
Phagocytosis:
Phagocytosis is the process by which cells bind and internalize particulate matter
larger than around 0.75 µm in diameter, such as small-sized dust particles, cell
debris,micro-organisms and apoptotic cells.
These processes involve the uptake of larger membrane areas than clathrin-
mediated endocytosis and caveolae pathway.

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Unit 2-plasma membrane and membrane transport

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Unit 2-plasma membrane and membrane transport