Transport across membranes

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Transport across membranes
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A Cell Membrane
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The cell membrane functions as a semi permeable
barrier, allowing a very few molecules across it
while fencing the majority of organically
produced chemicals inside the cell. Electron
microscopic examinations of cell membranes have
led to the development of the lipid bilayer
model (also referred to as the fluid-mosaic
model). The most common molecule in the model is
the phospholipid, which has a polar (hydrophilic)
head and two nonpolar (hydrophobic) tails. A
plasma membrane consists of a double layer of
phospholipid molecules arranged with their
hydrocarbon chains inwards. These phospholipids
are aligned tail to tail so the nonpolar areas
form a hydrophobic region between the hydrophilic
heads on the inner and outer surfaces of the
membrane.
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Diagram of a phospholipid bilayer
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The cell membrane is one of the organelles of a
cell. Cell membranes help organisms maintain
homeostasis by controlling what substances may
enter or leave the cells. The cell membrane is
said to be selectively permeable or
semi-permeable membrane. Some substances such
as water, oxygen, and carbon dioxide, can cross
the cell membrane without any input of energy by
the cell. The movement of such substances across
the membrane is know as passive transport.
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Drawing of a cell membrane

A component of every biological cell, the
selectively permeable cell membrane (or plasma
membrane or plasmalemma) is a thin and structured
bilayer of phospholipid and protein molecules
that envelopes the cell. It separates a cell's
interior from its surroundings and controls what
moves in and out. Cell surface membranes often
contain receptor proteins and cell adhesion
proteins. There are also other proteins with a
variety of functions.
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There are two major components of this dynamic,
fluid, structure lipids and proteins. A lipid
bilayer provides the basic structure within which
proteins are free to diffuse. Sugar
moieties can be present as part of either
proteins (glycoproteins) or lipids
(glycolipids). A further important component is
cholesterol which intercalates between lipid
molecules and affects membrane fluidity/stability.
Cholesterol is embedded in the hydrophobic
areas of the inner (tail-tail) region. Most
bacterial cell membranes do not contain
cholesterol.
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The cell membrane
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Fluid Mosaic model

• Proteins "float" in a 2-dimensional sheet of
  lipids.
• Composition of typical membrane
• 50 lipid (largely phospholipid in animal
  cells, 1/3 cholesterol)
• 50 protein
• Proteins function in variety of ways. Some are
  integral span entire membrane. Include transport
  proteins (permeases).
• Some are peripheral include receptor proteins
  for hormones, matrix of structural proteins that
  attach to membrane and provide shape, etc.

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Proteins are suspended in the inner layer,
although the more hydrophilic areas of these
proteins "stick out" into the cells interior as
well as the outside of the cell. These
integral proteins are sometimes known as gateway
proteins. Proteins also function in cellular
recognition, as binding sites for substances to
be brought into the cell, through channels that
will allow materials enter the cell via a passive
transport mechanism, and as gates that open and
close to facilitate active transport of large
molecules.
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• As a lipid bilayer, the cell membrane is
  selectively permeable.
• This means that only some molecules can pass
  unhindered through the gaps between the
  phospholipidsin or out of the cell.
• These molecules are either small or fat-soluble
  (lipophilic). Other molecules can pass in or out
  of the cell, if there are specific transport
  molecules.
• Depending on the molecule, transport occurs by
  different mechanisms, which can be separated into
  those that do not consume energy in the form of
  ATP (passive transport) and those that do (active
  transport).

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• Types of passive transport
• Osmosis - passive transport of water
• Diffusion - passive transport

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• Fat-soluble molecules, such as glycerol, can
  diffuse through the membrane easily. They
  dissolve in the phospholipid bilayer and pass
  through it in the direction of the concentration
  gradient, from a high concentration to a low
  concentration.
• Water, oxygen and carbon dioxide can also
  diffuse through the bilayer, passing easily
  through the temporary small spaces between the
  'tails' of the phospholipids.

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• Water soluble molecules and ions make use of
  membrane proteins.Some of these proteins have
  pores in them. Ions often pass through these
  pores. Gates open and close regulating the
  passage of the ions.Facilitated diffusion and
  active transport make use of protein carriers.

A carrier protein will have a specific
binding site for the substance it
transports.

• Solute molecules moving about on either side
  of the membrane will randomly come into contact
  with their specific binding site. Once they bind,
  the protein changes shape and the molecules come
  off the binding site on the other side of the
  membrane.

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• Osmosis
• One substance moves easily through the shifting
  lipids - molecules of water. Temporary gaps
  between the rapidly moving phospholipids make the
  membrane permeable to water molecules. However,
  the gaps are too small for larger molecules to
  get through.
• Being surrounded by a selectively permeable
  membrane has consequences. If more water enters
  the cell than leaves, the cell swells up. If more
  water leaves than enters, the cell shrinks.
• This movement of water through a selectively
  permeable membrane is known by one of the big
  words of biology - osmosis.

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If uncharged solutes are small enough, they can
move down their concentration gradients directly
across the lipid bilayer itself by simple
diffusion. Examples of such solutes are ethanol,
carbon dioxide, and oxygen. Most solutes,
however, can cross the membrane only if there is
a membrane transport protein (a carrier protein
or a channel protein) to transfer them. Passive
transport, in the same direction as a
concentration gradient, occurs spontaneously,
whereas transport against a concentration
gradient (active transport) requires an input of
energy. Only carrier proteins can carry out
active transport, but both carrier proteins and
channel proteins can carry out passive transport.

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The three types of passive transport are
diffusion osmosis
facilitated diffusion
Diffusion is the spontaneous movement of
particles from an area of higher concentration
to an area of lower concentration.
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Types of passive transport
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The transport proteins integrated into the cell
membrane are often highly selective about the
chemicals they allow to cross. Some of these
proteins can move materials across the membrane
only when assisted by the concentration gradient,
a type of carrier-assisted transport known as
facilitated diffusion. Both diffusion and
facilitated diffusion are driven by the potential
energy differences of a concentration gradient.
Glucose enters most cells by facilitated
diffusion.
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Passive transport
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  PASSIVE TRANSPORT where molecules move from an
area of high concentration to an area of low
concentration without the use or input of energy
by the cell, this process is known as diffusion. 
Diffusion is driven entirely by the kinetic
energy the molecules possess.
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The difference in the concentration of molecules
across a space is called a concentration
gradient.
If these molecules diffusing across the membrane
from an area of high concentration to an area of
low concentration were water molecules the
process would be called osmosis.  Water also
moves from a low solute concentration to a high
solute concentration.
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• Facilitated diffusion of ions takes place through
  proteins, or assemblies of proteins, embedded in
  the plasma membrane. These transmembrane proteins
  form a water-filled channel through which the ion
  can pass down its concentration gradient.
• The transmembrane channels that permit
  facilitated diffusion can be opened or closed.
  They are said to be "gated".
• Some types of gated ion channels
• ligand - gated (nicotinic acetylcholine receptor)
• mechanically - gated
• voltage - gated
• light - gated

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Ligand gated channels open or close in response
to the binding of a small signalling molecule or
"ligand". Some ion channels are gated by extra
cellular ligands some by intracellular ligands.
In both cases, the ligand is not the substance
that is transported when the channel opens. The
binding of neurotransmitter acetylcholine opens
sodium channels in certain synapses.
Mechanically gated channels - stretch receptors,
opening channels to create nerve impulses form
one such example.
Voltage gated channels are found in neurons and
muscle cells. They open or close in response to
changes in the charge (measured in volts) across
the plasma membrane. For example as an impulse
passes down a neuron, the reduction in the
voltage opens sodium channels in the adjacent
portion of the membrane. This allows the influx
of Na into the neuron and thus the continuation
of the nerve impulse.
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ACTIVE TRANSPORT. In many cases, cells must move
materials up their concentration gradient, from
and area of lower concentration to an area of
higher concentration. Such movement of materials
is known as active transport. Unlike passive
transport, active transport requires a cell to
expend or use energy usually in the form of
ATP. . There are three types of active transport
cell membrane pumps, endocytosis, and exocytosis.

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Types of active transport
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Types of transport molecules
Uniport transports one solute at a time.
Symport transports the solute and a cotransported
solute at the same time in the same direction.
Antiport transports the solute in (or out) and
the co-transported solute in the opposite
direction. One goes in the other goes out or
vice-versa.
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THE ACTIVE TRANSPORT PORCESS OF ENDOCYTOSIS
There are two types of endocytosis
pinocytosis-the transport of solutes or fluids,
and phagocytosis-the transport of large
particles, whole cells, or solids. During
endocytosis, (1,2)the cell membrane folds in and
forms a small pouch. The pouch then (3) pinches
off from the cell membrane to become a vesicle.
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THE ACTIVE TRANSPORT PROCESS OF EXOCYTOSIS.
During exocytosis, (1) a vesicle moves to the
cell membrane,(2) fuses with it,(3) and then
releases it contents to the outside of the cell.
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Exocytosis
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Phagocytosis

• a lung (alveolar) macrophage is seeking foreign
  bacteria (Escherichia coli) with specialized cell
  extensions called filopodia. Macrophages engulf
  and digest foreign materials in a process known
  as phagocytosis.

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ACTIVE TRANSPORT USEING A SODIUM
POTASSIUM PUMP
The SODIUM POTASSIUM PUMP actively pumps sodium
out of the cell and actively pumps potassium into
the cell, creating an electrical gradient across
the cell membrane. That is, the outside of the
membrane becomes positively charged and the
inside of the membrane becomes negatively
charged. This difference in charge is important
for the conduction of electrical (nerve) impulses
along nerve cells - neurons.
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Step 1  
 

• 3 Na ions bind to the ATPase under conditons of
  low Na concentrations because ATP and the
  transport protein has a high affinity for Na.
  This means the protein will bind Na ions even
  when the Na concentration is low.

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Step 2

• The transport protein cleaves ATP into ADP and
  Phosphate ion.The phosphate ion becomes
  covalently bonded to the protein.The
  phosphorylation of the protein causes it to
  become energetically unstable and the protein
  changes conformation.The shift in conformation of
  the protein in some manner causes the Na to
  travel across the protein and they are released
  from the protein on the other side of the
  membrane because the protein now has a low
  affinity for Na .  

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Step 3

• K ions bind to the protein even it there is a
  low K concentration because in this conformation
  the protein has a high affinity for K ions. The
  covalently bound phosphate group is cleaved from
  the protein which causes the protein to undergo
  another conformational shift.

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Step 4

• This conformational shift causes the K to be in
  some manner transported across the protein and
  released on the other side of the membrane. The
  K ion is released because now the protein has a
  low affinity for K ions. The protein is restored
  to the orginal conformation of the protein and
  the process starts again

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There are two general categories of receptor
proteins ionotropic and metabotropic.
Activation of ionotropic receptors causes
membrane ion channels to open or close. In
contrast, activation of metabotropic receptors
involves an intracellular biochemical cascade.
Such a cascade may end with the opening or
closing of ion channels or other intracellular
effects.
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Sodium Channels
The protein has 4 homologous domains containing
multiple potential a-helical transmembrane
segments. The segments are connected by
non-conserved, hydrophilic intervening segments.
The fourth transmembrane segment (S4) of each
domain is highly positively charged, and thought
to be a voltage sensor.
A sodium channel with four repeating units. It is
thought each domain folds into six transmembrane
helices. The orange filled circles on the
connecting segments between S5 and S6 represents
a TTX binding site. An inactivation gate (IG)
exists between domains III and IV.
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Sodium Channels Voltage gated sodium channels are
crucial for the propagation of action potentials
in excitable membranes. They cause the cell
membrane to depolarise by allowing the influx of
sodium ions into the cell. Some 7000 sodium ions
pass through each channel during the brief period
(about 1 millisecond) that it remains open.
Voltage gated sodium channels consist of an
a-subunit responsible for selectivity and voltage
gating. However some sodium channels also have
one or two smaller subunits called ß-1 and ß-2.
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In order to repolarise the cell, the sodium
channels must be impermeable to Na. This is
achieved by an inactivation phase.
The cytoplasmic link between domain III and
domain IV is responsible for this inactivation
according to the "ball and chain" model.
A binding site on the sodium channel causes
conformational changes when bound with the
inactivation gate, thus closing the channel to
Na ions.
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Second Messengers
Definition A diverse family of low molecular
weight compounds such as cyclic AMP and calcium
ions, which transmit the biological signals
initiated by receptor-ligand binding at the cell
surface to intracellular targets such as gene
expression. Examples of second messenger
systems are the adenyl cyclase-cyclic AMP system,
the phosphatidylinositol diphosphate (PIP2)
-inositol triphosphate system (IP3), and the
cyclic GMP system. Systems in which an
intracellular signal is generated in response to
an intercellular primary messenger such as a
hormone or neurotransmitter. They are
intermediate signals in cellular processes such
as metabolism, secretion, contraction,
phototransduction, and cell growth.
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Second Messengers inside the cell Many different
kinds of molecules can serve as second
messengers. The signal, or ligand, binding to a
membrane receptor leads to the production of
second messengers inside the cell. The original
signal usually doesn't enter the cell. The small
molecule "cAMP" was the initial second messenger
to be identified. Other examples of second
messengers include NO, IP3, and DAG. The figure
below shows an example of the production of
second messengers.
The figure depicts a system where the signal
causes a G-protein to become active, stimulating
the membrane enzyme phospholipase C. This enzyme
degrades cell membrane phosphatidyl inositol
releasing IP3 (inositol triphosphate) and leaving
diacyl glycerol (glycerol with two fatty acids,
DAG). Both are second messengers, with IP3
causing the endoplasmic reticulum to release Ca
(also a second messenger). The DAG activates
protein kinase C, a kinase that is dependent on
Ca for activity. Note that both second
messengers play a role in the activation of
protein kinase C. The response made by the cell
will depend on what targets for protein kinase C
are available
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The second messenger activity of cAMP ends when
it is broken down by the enzyme
phosphodiesterase. Caffeine and theophylline (the
latter found mainly in tea) exert their
stimulatory effects by inhibiting
phosphodiesterase, and thereby preventing the
breakdown of the cAMP second messenger molecule.
Although cAMP is by far the most common second
messenger in brain neurons, there are many
others, including cGMP and the Ca2/calmodulin
complex.
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Glia cells

• Although glia cells DO NOT carry nerve impulses
  (action potentials) they do have many important
  functions. In fact, without glia, the neurons
  would not work properly!

Astrocytes, like most glial cells, were long
considered essential for their role in supporting
and maintaining nerve tissue. But more and more
evidence indicates that astrocytes may actually
play a far more important role in neural
communication
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The central nervous system consists of neurons
and glial cells.  Neurons constitue about half
the volume of the CNS and glial cells make up the
rest.   Glial cells provide support and
protection for neurons.  They are thus known as
the "supporting cells" of the nervous system. 
The four main functions of glial cells are - to
surround neurons and hold them in place - to
supply nutrients and oxygen to neurons - to
insulate one neuron from another - to destroy
and remove the carcasses of dead neurons
(clean up)
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Function of glia cells
Some glia function primarily as physical support
for neurons. Others regulate the internal
environment of the brain, especially the fluid
surrounding neurons and their synapses, and
provide nutrition to nerve cells. Glia have
important developmental roles, guiding migration
of neurons in early development, and producing
molecules that modify the growth of axons and
dendrites. Recent findings in the hippocampus
and cerebellum have indicated that glia are also
active participants in synaptic transmission,
regulating clearance of neurotransmitter from the
synaptic cleft, releasing factors such as ATP
which modulate presynaptic function, and even
releasing neurotransmitters themselves.
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The three types of CNS supporting cells are
Astrocytes Oligodendrocytes
Mikroglia The supporting cells of the PNS
are known as Schwann Cells
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Astrocytes
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Astrocytes, also known as astroglia, are
characteristic star-shaped, sub-type of the glial
cells in the brain. Their many arms span all
around neurons. They are the
biggest cells found in brain tissue and outnumber
the neurons ten to one.
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Astrocytes

• Astrocytes are star-shaped glial cells of the CNS
  that have long processes. Many of these processes
  extend to blood vessels where they expand and
  cover much of the external wall. The expanded
  endings of the astrocyte processes are known as
  end-feet. While the blood-brain-barrier is formed
  by tight junctions between endothelial cells, the
  end-feet function to induce and maintain the
  blood-brain barrier. In pathology following
  stroke the relationship of end-feet to the
  endothelial cells is altered leading to
  disruption of the blood-brain barrier and
  subsequent leakage.

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Astrocytes
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• Classification
• Type I Those astrocytes are in direct contact
  with blood capillaries through astrocytique pod.
  They are actively helping neuronal metabolism and
  glucose delivery.
• Type II Type II atrocytes surrounds neurones and
  synaptic gap. This coverage varies from 1 to
  100.
• Anatomical Classification
• Protoplasmic found in grey matter and have many
  branching processes
• Fibrous found in white matter and have long thin
  unbranched processes

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The fibrous astrocyte
The fibrous astrocyte (A) is found in association
with nerve fibers.
Each astrocyte has numerous processes (B), some
astrocytic processes are in contact with nerve
fibers. Other astrocytic processes surround
capillaries (D) forming perivascular end-feet
(C).
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Schwann Cells
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Schwann cells are the supporting cells of the
PNS (peripheral nervous system). Like
oligodendrocytes Schwann cells wrap themselves
around nerve axons, but the difference is that a
single Schwann cell makes up a single segment of
an axon's myelin sheath. This arrangement permits
saltatory conduction of action potentials which
greatly speeds it and saves energy.
Oligodendrocytes on the other hand, wrap
themselves around numerous axons at once.
Schwann cells are the peripheral nervous
system's analogues of the central nervous system
oligodendrocytes. In addition to creating the
myelin sheaths of PNS axons, Schwann cells having
phagocytotic activity, aid in cleaning up PNS
debris and guide the regrowth of PNS axons.  To
do this Schwann cells arrange themselves in a
series of cylinders that serves as a guide for
sprouts of regenerating axons. 
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Oligodendrocyte
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A microglial cell
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Microglia
Microglia are specialized macrophages
capable of phagocytosis that protect neurons of
the CNS. They are derived from monocytes
rather than ectodermal tissue. Microglial
cells are small relative to macroglial cells,
with changing shapes and oblong nucleus.
They are mobile within the brain. These
cells, while normally only existing in small
numbers, multiply in case of damage in the
brain.
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Blood-Brain Barrier
The blood-brain barrier (BBB) is the specialized
system of capillary endothelial cells that
protects the brain from harmful substances in the
blood stream, while supplying the brain with the
required nutrients for proper function.
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• Functions of the BBB
• Protects the brain from "foreign substances" in
  the blood that may injure the brain.
• Protects the brain from hormones and
  neurotransmitters in the rest of the body.
• Maintains a constant environment for the brain.
  

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The BBB can be broken down by

• Hypertension (high blood pressure) high blood
  pressure opens the BBB
• Development the BBB is not fully formed at
  birth.
• Hyperosmolitity a high concentration of a
  substance in the blood can open the BBB.
• Microwaves exposure to microwaves can open the
  BBB.
• Radiation exposure to radiation can open the
  BBB.
• Infection exposure to infectious agents can
  open the BBB.
• Trauma, Ischemia, Inflammation, Pressure
  injury to the brain can open the BBB.

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Circumventricular Organs There are
several areas of the brain where the BBB is weak.
This allows substances to cross into the brain
somewhat freely. These areas are known as
"circumventricular organs" (barrier-deficient
areas). The circumventricular organs (CVO's) are
midline structures bordering the 3rd and 4th
ventricles and are unique areas of the brain that
are outside the blood-brain barrier (BBB). The
circumventricular organs include Pineal
body Neurohypophysis (posterior pituitary)
Area postrema ("Vomiting center) Vascular
organ of the lamina terminalis Subfornical
organ Median eminence
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