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physiology
--- Structure & Function of plasma
membrane and its role in drug Absorption.
Kiran.D
Dept. of pharmaceutics,
University College of Pharmaceutical Sciences,
Kakatiya University, Warangal-506009
Content
• Introduction
• Physiology of Plasma membrane.
–
–
–
–
Structure,
composition,
functions.
Transport across cell membrane.
• Conclusion
• References
Plasma membrane structure
• Definition:
The Plasma membrane is a thin bilayered structure which surrounds each cell,
consists of lipids (phospholipids 75%, cholesterol
20%,glycolipids 5%), proteins (partially or
completely embedded), carbohydrates etc.,
• ~6-10 nm thick.
• Plasma membrane is asymmetrical
Membrane Models
• Robertson- Unit membrane
• Singer and Nicolson - Fluid-Mosaic Model
- Membrane structure is not rigid (fluid)
- Membrane comprised of diff. molecules (mosaic)
- Proteins float around the surface of the cells
- Proteins, Carbohydrates, Phospholipids can be
added/removed from the surfaces of cells
FLUID MOSAIC MODEL
The fluid mosaic model describes the plasma membrane as a flexible boundary of a
cell. The phospholipids move within the membrane.
FLUID- because individual phospholipids and proteins can move around freely
within the layer, like it’s a liquid.
MOSAIC- because of the pattern produced by the scattered protein molecules
when the membrane is viewed from above.
Plasma Membrane
Phospholipids
• Phospholipids are lipids with a
phosphate attached to them.
• The phospholipids are very flexible and
behave similar to a fluid.
• The lipids in the plasma membrane can
be saturated or unsaturated, the more
saturated lipids in a membrane the more
rigid the plasma membrane is. The more
unsaturated lipids, the more flexible the
membrane is.
• The phospholipids have a water soluble
head, and water insoluble lipid tails.
Figure 5.12 -- Phospholipids contain 2 fatty acids, glycerol,
phosphate, and an alcohol linked by ester bonds
The lipids in a
plasma membrane
have a glycerol
backbone, two
fatty acid chains,
and a phosphate
group.
The phosphate
group is critical for
the formation and
function of the
plasma
membrane.
Phosphate Group
Glycerol
Backbone
Two Fatty
Acid
Chains
Other lipids in plasma membrane
• GLYCOLIPIDS: Phospholipid molecule attached with a
carbohydrate chain straight or branched to its hydrophilic head.
• CHOLESTEROL: lipid found in animal plasma membranes which
reduces the permeability to most biological molecules.
• it regulates membrane fluidity over the range of physiological
temperatures.
• cholesterol also functions in intracellular transport, cell signaling and
nerve conduction.
• cholesterol has also been implicated in cell signaling processes,
assisting in the formation of lipid rafts in the plasma membrane.
• In many neurons a myelin sheath, rich in cholesterol since it is
derived from compacted layers of Schwann cell membrane, provides
insulation for more efficient conduction of impulses.
• Cholesterol present between the fatty acids chains, binds with OH
side to the phosphate of lipid by H-bonding.
MEMBRANE PROTEINS
• Each cell: 10-50 different types of membrane proteins.
• Proteins determine membrane’s specific functions.
• Cell membrane & organelle membranes each have unique collections
of proteins.
Peripheral proteins (Cell surface identity marker (antigens))
• present either to the outside or inside of the cell.
• Some of them are anchored to the membrane by covalent bonding.
• Others held non-covalently that can be disrupted by gentle movement or
change in pH.
• Include enzymes and binding proteins that anchor cell to membrane.
Integral proteins (Transmembrane proteins)
- Tightly bound to phospholipid bilayer.
- Present within the matrix of the membrane.
oligosaccharide
cholesterol
groups
phospholipid
EXTRACELLULAR ENVIRONMENT
(cytoskeletal proteins beneatch
ADHESION
the plasma
PROTEIN
membrane)
open
gated
channel channel
protein proten
(open)
gated
channel
proten
(closed)
(area of
enlargment)
TRANSPORT PROTEINS
PLASMA MEMBRANE
active
transpor
t protein
RECEPTOR
PROTEIN
LIPID BILAYER
RECOGNITION
PROTEIN
CYTOPLASM
Membrane carbohydrates
 Play a key role in cell-cell recognition
(The carbohydrate chains of glycolipids and glycoproteins
serve as the “fingerprints” of the cell).
 Glycolipids and glycoproteins vary from species to
species and even from cell to cell in the same individual.
– ability of a cell to distinguish one cell from another.
– important in organ & tissue development.
– basis for rejection of foreign cells by immune system.
– Person’ particular blood group is due to the presence
of particular glycoproteins in the membrane of RBC.
Fluidity of plasma membrane
• At body temperature plasma
membrane has the consistency of
olive oil.
• The greater the concentration of
unsaturated fatty acids residues,
the more fliud is the bilayer.
• The hydrocarbon tail of
phospholipid molecule wiggle and
the entire phospholipid molecule
can move sideways at a rate of
2µm per second.
• Some phospholipids rarely flip-flop
from one layer to the other.
• Cholesterol which is wedged
between phospholipids molecules
in the plasma membrane of
animals cells, restrains the
movement of the phospholipids in
warm temps and maintains fluidity
by preventing tight packing at cold
temps thereby add support and
rigidity to the membrane.
functions
•
•
•
•
•
•
Physical isolation - Separates inner and outer environment, surrounds &
gives cell a particular shape.
Lipids restricts passage of polar compounds.
Proteins customize membranes
– Provide structural support
– Serve as transporters, enzymes, receptors & identity markers
Regulates exchange with the environment - membrane channel proteins +
carrier proteins.
Carbohydrates in form of glycoproteins & glycolipids are part of outer
surface Impart negative charge to surface (cell recognition) (glycocalyx).
Allows a steady supply of glucose, amino acids, and lipids to come into the
cell.
•
Maintains concentration gradient across the membrane.
•
•
Maintains electrochemical gradient across the membrane.
“homeostasis” Sensory receptor - membrane receptor proteins sense
changes in external environment (encrusted with peripheral nerves).
Other components of the plasma membrane
Cholesterol plays the important role of
preventing the fatty acid chains of the
phospholipids from sticking together.
Cholesterol
Molecule
Protein Functions
• Channel Proteins - Involved in passage of molecules
or ions through membrane.
• Carrier Proteins - Combine with substance to aid in
passage through membrane.
• Cell Recognition Proteins - Help body recognize
foreign substances. MHC (major histocompatabilty
complex) glycoproteins, are difficult for each person,
therefore rejected at the time of organ transplantation.
• Receptor Proteins – Shaped in such a way that a
specific molecule can bind to it. It may sometimes cause
protein to change shape and bring about the transport.
• Enzymatic Proteins – Catalyse a specific
reaction.(adenylate cyclase involved in ATP synthesis)
Classes of Amino acids
What do these amino acids have in common?
Nonpolar & hydrophobic
Classes of amino acids
What do these amino acids have in common?
Polar & hydrophilic
Proteins domains anchor molecule
• Within membrane
– nonpolar amino acids
• hydrophobic
• anchors protein
into membrane
Polar areas
of protein
• On outer surfaces of membrane
– polar amino acids
• hydrophilic
• extend into extracellular
fluid & into cytosol
Nonpolar areas of protein
Transport Across Plasma
Membrane
• Selectively permeable.
• Passive
Diffusion,
Osmosis,
Facilitated diffusion
• Active
Primary active transport,
Secondary active transport.
Diffusion
•
•
•
•
•
•
Movement of molecules from higher concentration to a lower
concentration( down the gradient), until equilibrium is attained.
Non-polar highly polar compounds readily diffuse through cell
membrane.
Most drugs follow this type of transport.(90%)
Size of molecule 100-200 D.
First order kinetics.
ex: Fatty acids, steroids vitamins, etc.,
Osmosis (pore transport, aquaporins)
• The process of water
moving from low solute
concentration to high solute
concentration across a
semi-permeable membrane
is called osmosis.
• Upto 100 D, 0.4nm.
• Ex: Highly water soluble
drugs, drugs entering liver,
renal excretion, removal of
drugs from CSF.
Solute: particles dissolved
in water : Fe, Mg, O2, etc.
Ion channels
•
Charged & most polar compounds
must have an ion channel or
transporter to move across membrane
• Ion channels are integral proteins,
which conduct ions like Na+, K+
,Ca+2
• They can differentiate between the
size and charge of the ion that is
being diffused.
• They may open or gated and
depend on chemical, electrical or
mechanical signals for the transfer
of a specific molecule across the
membrane.
Facilitated diffusion
•
•
•
•
•
•
•
Involves special carrier protein for the transfer of
molecule across the membrane.
These carriers are specific only to a particular
molecule.
Once the molecule binds to the protein a
conformational change occurs in the protein, which
moves the molecule down its concentration
gradient.
Saturation or transport maximum.
Specific
Competition
Mixed order kinetics.
Active transport
•
•
•
•
•
•
•
Across the concentration gradient.
Consumes 40% of the cell energy.
Selective
Saturation
Competition.
Specific in location.
Ex: thiamine, nicotinic acid,
riboflavin, pyridoxine, 5-floro uracil,
methyl dopa, nicotinamide.
• Two types:
Primary
Secondary
Primary Active Transport:
1) Na+/K+
Pump:
 Present in thousands per cell.
 Helps maintain sodium on the
outside and potassium inside.
 When three Na+ ions bind to the
protein the ATP-pase function of
the protein becomes activated.
splitting of ATP to ADP and high
energy phosphate. High energy
phosphate causes
conformational change helps
moving Na+ ions outside of the
cell and brings 2 K + ions into the
cell.
• Secondary Active Transport:
 Co-transport or Symport: The diffusion gradient of Na+ can pull
other molecules along with it, this is called co-transport or symport.
ex: glucose-sodium pump, lactose-proton pump,
sodium-amino acid pump, sodium-proton pump.
 Antiport or Counter transport: The diffusion gradient of Na+
exchanges other molecules with it, this is called Antiport or Counter
transport.
1) Na+/ Ca+ pump
Transport of large particles
Endocytosis- A cell surrounds material and takes it in from its
environment by enclosing it in a newly formed vacuole.
3 types:
1) Receptor-mediated endocytosis-vitamins
antibodies,hormones, virus.
2) Phagocytosis.
3) Bulk phase endocytosis.
Figure 8.18 The three types of endocytosis in animal cells
Transport of drugs
• 2 super families.
• ABC (ATP binding cassette)-active
• SLC (solute carrier)-facilitated
ABC:
• Active transport
• Divided into 7 subclasses (or) families (A-G)
These include
1) P-gp (encoded as ABCB1/MDRI).
2) Cystic Transmembrane CFTR regulator(ABCC7).
SLC:




Facilitated Transport.
Ion coupled.
43 SLC Families, 300 Transporters.
Seratonin SERT, (SLC6A4), Dopamine Transporters, DAT(SLC6A3).
Factors responsible for drug
absorption across the membrane
•
•
•
•
•
•
•
Molecular size
Shape
Degree of ionization
Surface area of exposed membrane exposed.
Relative solubility of ionized & unionized forms.
Concentration gradient across the membrane.
Receptor availabilty.
Conclusion
References
• Principles of Anatomy & Physiology,
Gerard.J.Tortora, Bryan Derrickson.
• Pharmacology, H.P.Rang, M.M.Dale.
• The Pharmacological Basis Of Therapeuctics,
Goodman’s and Gilman’s.
• Biopharmaceutics and Pharmacokinetics,
D.M.Bramhankar, Sunil B.Jaiswal.
• www.sciencedirect.com
• www.pubmed.com
• www.pharmacorama.com
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