PLM College of Medicine

2019

1A

1.01

16, June, 2015

BIOCHEMISTRY

Dr. Geraldine Susanne C. Tengco| Cell and Cell Membrane

Transcribers: Maano, Delos Reyes, Fernandez, Flores, Guevarra, Javier, Lanuza, Libit, Molina, Pagatpatan

LEARNING OBJECTIVES

1.
2.
3.
4.

Describe the structure of the cell membrane.

Discuss the composition of the cell membrane.
Discuss its functions.
Describe the general features of the fluid mosaic
model of membrane structure.
5. Discuss the different membrane processes and
the factors affecting them.
6. Differentiate micelle from liposome.
7. Describe the process of membrane assembly.

4.
5.
6.
7.
8.

(i.e. exchange of materials through endocytosis

and exocytosis, cell communication through the
nervous system and hormones)
Transmembrane signaling
Compartmentalization (organelles)
Enzyme Localization
Excitation-response coupling
Energy transduction

CELL MEMBRANE
Highly fluid, dynamic (exhibits rapid turnover and
lateral diffusion)
Asymmetric, sheet-like structures with inner and
outer surfaces
Viscous, plastic structures
o Ex. Red blood cells that have to pass
through sinusoid should be pliable.
Thermodynamically stable and metabolically
active
Noncovalent assemblies composed of lipids,
proteins and carbohydrates.
ASYMMETRY OF CELL MEMBRANE
INSIDE-OUTSIDE SYMMETRY
Irregular distribution of proteins
External location of carbohydrates
Specific enzymes exhibit specificity of location
Phospholipids (choline containing are external
while amino acid containing are in the inner leaflet)

MAJOR BODY COMPARTMENTS

Body = 60% water
1. INTRACELLULAR FLUID (ICF)
2/3 of TBW
Provides environment for the cell to
o Synthesize, store and utilize energy
o Repair itself
o Replicate
o Perform special functions
2. EXTRACELLULAR FLUID (ECF)
1/3 of TBW
2 compartments: PLASMA and
INTERSTITIAL FLUID
delivery system of nutrients, ions, oxygen
and hormones to cells
Removes waste products from the cells

REGIONAL ASSYMETRIES
Villous borders (i.e. villi found in the small
intestin, microvilli found in the ears and
fallopian tubes)
Gap junctions
Tight junctions
FUNCTIONAL PROPERTIES
1. Cell Individuality
2. Selective permeability (channels, transporters and
pumps)
3. Cell-cell interaction and adhesion

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INTRACELLULAR
(High in)
+
K
2+
Mg
Proteins
Major anion: Phosphate

Simplest phosphoglyceride is phosphatidic

acid.

EXTRACELLULAR
(High in)
+
Na
2+
Ca
Glucose
Major Cation: Chloride

MEMBRANE LIPIDS
All major membrane lipids are amphipathic (have
both hydrophobic and hydrophilic regions)
Forms a lipid bilayer that is impermeable to watersoluble molecules.
Need for channels and transporters.
Lipid bilayers are formed by self-assembly driven
by hydrophobic effect

B. Sphingomyelin
Second major class of phospholipid
Sphingosine instead of glycerol is its
backbone
Ceramide = sphingosine + fatty acid
Hydroxyl group of sphingosine is esterified
to phosphorylcholine
Sphingomyelin is prominent in myelin
sheath

FATTY ACIDS
Saturated with straight tails (resulting to more rigid
cell membranes).
Unsaturated fatty acids have kinked tails (more
fluid membranes).
3 MAJOR MEMBRANE LIPIDS
1. PHOSPHOLIPIDS - lipids with phosphate groups.
A. Phosphoglycerides
Most common phospholipid
Consists of a glycerol backbone to which
are attached two fatty acids in ester
linkage and a phosphorylated alcohol like
ethanolamine, choline, serine, glycerol or
inositol.
Fatty acids are even-numbered (16-18 C
atoms) which could be saturated or
unsaturated.

2. GLYCOSPHINGOLIPIDS - sugar containing lipids built

on a backbone of ceramide.
Cerebrosides
Gangliosides
3. STEROLS
The most common of which is cholesterol
Modifies membrane fluidity
"moderator molecule"
Increases fluidity at temperatures below
Tm; Limits disorder at temperatures above
Tm

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MEMBRANE PROTEINS
The major functional molecules of membranes
Amphipathic: hydrophilic regions are protruding at
the inside and outside faces of the membrane but
connected by a hydrophobic region traversing the
hydrophobic core of the bilayer
Different membranes have varying protein
compositions
Functions of membrane proteins:
o Enzymes
o Pumps, channels, carriers
o Antigens
o Receptors
o Structural Proteins
Types of Membrane Proteins:
o Integral proteins:
Interact extensively with
phospholipids
Require detergents for
solubilization
Amphipathic, globular and, in
certain proteins, spans the
bilayerseveral times (eg, G
proteins)
Asymmetrically distributed in cell
membrane
The orientation was conferred by
the time of insertion to the bilayer
during synthesis in the ER
Most membrane proteins fall
under integral proteins
o Peripheral proteins
Do not interact directly with
phospholipids (do not require
detergents for release)
Weakly bound to hydrophilic
regions of integral proteins on one
side of the membrane
Ex: Ankyrin is bound to integral
protein Band 3; spectrin is in turn
bound to ankyrin (Figure 1).
MEMBRANE CARBOHYDRATES
Occur in association with lipids or proteins:
o Glycolipids
o Glycoproteins
Mostly found on the external membrane surface
Functions:
o Receptors

o
o

Antigens
Confers negative charge to cell (as
glycocalyx)

RBC cystoskeletal proteinsspectrin and ankyrin with emphasis on their

interactions.

FLUID MOSAIC MODEL

Universally accepted description of membrane

structure coined by singer and Nicolson (1972)
Lipid bi-layer with embedded proteins (trilaminar
under electron microscope)
icebergs (proteins) floating in a sea of
phospholipids
Membrane lipids = fluid part
Membrane proteins = mosaic part
Membranes undergo changes from stiff (gel or
crystalline) to fluid state
Proteins and lipids undergo rapid redistribution
(lateral diffusion)

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MEMBRANE FLUIDITY
critical to its function; some cells have acquired
the ability to vary the fluidity of their membranes
as needed
Factors that affect membrane fluidity:
1. Lipid composition
longer and more saturated fatty acid chains exhibit
higher transition temperature
Unsaturated fatty acids create a kink (bend)
Prevents fatty acids from packing together as
tightly
Decreases the melting temperature (increasing the
fluidity) of the membrane
2. Temperature
Transition Temperature (Tm) - temp at which
structure undergoes transition from ordered to
disordered state
* high temperatures = more fluid
* low temperatures = hydrophobic side chains
become aligned --> stiff structure

ARTIFICIAL MEMBRANES & OTHER SPECIAL

MEMBRANE STRUCTURES
MICELLES
Small aggregates of amphipathic molecules that
form a monolayer with
o Hydrophobic regions shielded from
H2OHydrophilic regions immersed in
H2O
The arrangement of the two regions depends on
the chemical environment where the micelle is
located.
In a polar environment, the hydrophilic region is
facing the solution and the hydrophobic regions
are situated in the interior of the micelle.
Conversely, in a non-polar environment, the
hydrophilic region is found in the interior while the
hydrophobic region faces the solution (inverse
micelle).

3. Cholesterol
moderator molecule
T above Tm, fluidity due to its rigid structure
(condensing effect)
T below Tm, fluidity (induces disorder)
Importance of Membrane Fluidity
Permeability to water and other hydrophilic
molecule increases
Lateral mobility of integral proteins increases*
o especially for transport and receptor
proteins

CLINICAL APPLICATION OF MICELLES

Formed when bile acids, which are amphipathic,
associate with products of lipid digestion
Bile acids forms micelles that assist in the
digestion and absorption of fat and vitamins A, D,
E, and K
LIPOSOMES: ARTIFICIAL MEMBRANES
Vesicles that are surrounded by a lipid bilayer
Consists of phospholipids that can be natural or
synthetic in origin

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Uses:
o
o
o

Lipid content can be varied for the

examination of varying lipid composition
on certain functions (i.e. transport)
Study of factors that affect protein and
enzyme function
May be used for specific drug delivery and
gene therapy
TIGHT JUNCTIONS

Located below the apical surface of epithelial cells

Prevent diffusion of macromolecules between
them
Composed of proteins occludin, claudins
Route for paracelullar transport

GAP JUNCTIONS
Low resistance connections between the cells
Allow the movement of ions and small molecules
between the cells
Adjacent cells are coupled electrically
Connexon functional unit of gap junction
The alignment of a connexon of one cell with the
connexon of other cell forms a channel

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LIPID RAFTS
Dynamic areas of the exoplasmic leaflet of the
lipid bilayer enriched in cholesterol, sphingolipids,
and proteins
Involved in and enhances signal transduction by
clustering the elements of signaling systems

PASSIVE TRANSPORT
Some molecules can passively traverse the bilayer
down electrochemical gradients by simple
diffusion or by facilitated diffusion

SIGNAL TRANSDUCTION
Signal transmission across the membranes
Biochemical signals from hormones,
neurotransmitters bind to receptors in cell
membrane
Through the generation of signaling moleculesm
the information is transmitted to the cytoplasm.
Signaling molecules:
o Cyclic nucleotides
o Calcium
o Diacylglycerol
o Phosphoinositides

TRANSPORT SYSTEM
Transfer of solutes and information across membranes.
Importance of transport systems:
Cell membrane is selective
Cell membrane receives and transmits signals to
and from other cells
Transport System according to Direction of Movement
1. UNIPORT
moves one type of substance bidirectionally (ie. Glucose transported into
cell through influence of insulin.)
2. COTRANSPORT
SYMPORT - moves two solutes in the
same direction (ie. Glucose transported
+
together with Na )
ANTIPORT - moves two solutes in
+
++
opposite directions (ie. Na (in) and Ca
+
or H (out) and Cl HCO3 exchanger in
RBC membrane)

Unlike active transport, passive transport does not

require energy because it does not constitutes
movement against an electrochemical gradient.
SIMPLE DIFFUSION
Transport across the membrane down an
electrochemical gradient
No need for energy
Passive flow of a solute from a higher to lower
conc. due to random thermal movement
The difference between facilitated diffusion (FD) is
that FD is mediated by a specific protein
transporter
Movement via simple diffusion is limited by:
Thermal agitation of that specific molecule
Concentration gradient across the membrane
Solubility of that solute (permeability coefficient) in
the hydrophobic core of the membrane bilayer.
Involves kinetic energy of molecules
Factors affecting net diffusion:
1. Concentration across the membrane solutes
move from high to low concentration
2. Electrical potential across the membrane solutes
move toward the solution that has the opposite
charge (the inside of the cell is usually negative)
3. Permeability coefficient of the substance for the
membrane (lipid solubility)

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4. Hydrostatic pressure gradient across the

membrane higher pressure will increase the rate
and force of the collision between the molecules
and the membrane
5. Thickness of membrane the thinner the
membrane the greater the rate of diffusion
6. Temperature increased temperature will
increase particle motion and thus increase the
frequency of collisions between external particles
and the membrane
7. Distance
8. Number of channels
FACILITATED DIFFUSION
Involves either certain transporters or ion channels.
ION CHANNELS
for water soluble substances (ions) that cannot
just simply permeate the membrane
Permeability depends upon:
o Size
o extent of hydration
o charge density of the ion
o there are specific channels for each ion
o activity of some channels are regulated by
neurotransmitters
function can be impaired by disease/mutations
channels can be gated
+
+
2+
Specific channels for Na , K , Ca , and Cl have
been identified

Ion Channel Gating

1. Voltage Gating
channels open or close in response to changes in
membrane potential
ex. Sodium Channels
2. Ligand Gating
a specific molecule or chemical binds to a receptor
which opens the channel
ex. Use of neurotransmitters like Ach
3. Mechanical Gating
channel respond to mechanical stimuli (pressure
and touch)
AQUAPORINS
water channels found in certain cells : RBC, distal
tubules and collecting ducts of renal nephrons
tetrameric membrane proteins
5 distinct aquaporins : AP-1 to AP-5
mutation in AP-2 is the cause of nephrogenic
Diabetes Insipidus

Membranes of nerve cells contain ion channels

that are responsible for the generation of action
potential
Activity of some ion channels is controlled by
neurotransmitters

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CARRIER MEDIATED TRANSPORT

FACILITATED DIFFUSION

Facilitated diffusion and active transport are similar in the

following:
1. Involve carrier proteins
2. Show specificity for ions, sugars and amino acids
3. Carriers exhibit maximum transport (Vmax) or
saturability
4. There is binding constant (Km) for the solute

a uniport system
explained by the PING PONG mechanism
o ping state = carrier is exposed to high
concentrations of solute. Molecules of the
solute bind to specific sites on the carrier
protein
o pong state = carrier is exposed to a lower
concentration of solute. Solute is
discharged (released from binding) where
it goes to the side of the membrane that
favors the new equilibrium

The rate of facilitated diffusion, a uniport system, can be

saturated. Many facilitated diffusion systems are
stereospecific are driven by the transmembrane
electrochemical gradient.

in the ping state, the conformation of the protein

exposes the binding site to high concentration of
solute, the molecules of the solute bind to specific
sites on the carrier protein
the binding will cause a conformational change
(pong state) on the carrier protein which exposes
the binding site to the side of lower solute
concentration, the solute is discharged from the
carrier to achieve equilibrium
empty carrier reverts back to original conformation
(ping state again) completing the cycle
The rate at which solutes enter a cell by facilitated
diffusion is determined by:

The rate of movement in passive diffusion is directly

proportionate to solute concentration. The process is
saturable, however, when carriers are involved (carriermediated diffusion). The concentration at half maximal
velocity is equal to the binding constant (Km) of the carrier
for the solute. (Vmax, maximal rate.)

1.
2.
3.
4.

concentration gradient across membrane

amount of carrier available (key control step)
rapidity of solute-carrier interaction
rapidity of conformational change for both the
loaded and unloaded carrier
5. presence of certain hormones : Insulin, GH and
glucocorticoids
Hormones can regulate facilitated diffusion by changing
the number of transporters available.(i.e. insulin increases
glucose transport in fat and muscle by recruiting glucose
transporters (GLUT) from an intracellular reservoir.)

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2. Secondary active transport piggy-back

ACTIVE TRANSPORT
Transport is away from thermodynamic equilibrium (energy
requiring).
1. Primary active transport
Requires energy from light, electron movement
or ATP hydrolysis
energy for this process represents 30 40% of
energy expenditure of the cell
+ +
Ex: Na K ATPase
Is the transport of a solute across a membrane in
the direction of increasing concentration, and thus
requires energy (frequently derived from the
hydrolysis of ATP); a specific transporter (pump) is
involved
+

The Na K ATPase of the plasma membrane Is a Key

+ +
Enzyme in regulating intracellular concentrations of Na K .

Na K ATPase pump moves three Na ions from the

+
inside of the cell to the outside and brings two K ions from
the outside to the inside for every molecule of ATP
hydrolyzed to ADP by membrane associated ATPase
2+
(Mg is a cofactor)
+ +
ouabain and digitalis, inhibit the Na K ATPase by
binding to the extracellular domain.

OSMOSIS
the net flow of solvent across a semipermeable
membrane from an area of LOWER SOLUTE
CONCENTRATION to an area of HIGHER
SOLUTE CONCENTRATION
due to a semipermeable membrane that only
allows the solvent to pass
affected by osmotic pressure

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Osmotic Pressure
minimum pressure required to negate or reverse
osmosis.
force or pressure is applied on the side of the
membrane with higher solute concentration to
push the solvent back to the area with low solute
concentration
determined by the number of particles per unit
volume of fluid
volume may increase or decrease to
accommodate equilibrium if non-penetrating solute
is concerned
CELLULAR TRANSPORT OF MACROMOLECULES
involves vesicle formation with or from the plasma
membrane (PM)
Two process:
o endocytosis
o exocytosis
I. ENDOCYTOSIS
uptake of large molecules
o molecules taken up by the cell when
hydrolyzed yield nutrients
provides a mechanism for regulating the content of
certain membrane component (e.g. hormone
receptors)
responsible for DNA transfection (entry of DNA
into the cell)
o DNA from one cell transfecting a different
cell, altering the latters function and
phenotype
2+
2+
o uses Ca (Ca stimulates endocytosis
and precipitates DNA, making DNA a
better object for endocytosis)
involves macromolecules: proteins,
polysaccharides and polynucleotides
Requires the following:
o energy
2+
o Ca
o contractile elements/proteins
(microfilament system)

Types of endocytosis
1. PINOCYTOSIS
cellular uptake of fluid and fluid content
Two types of Pinocytosis:
a) Fluid-phase pinocytosis
also called cell drinking
is a nonselective process no
requirements
uptake of a solute thru small vesicle
formation that is proportionate to its
concentration in the ECF (extracellular
fluid)
is an active process (requires ATP)
b) Absorptive pinocytosis
is a receptor-mediated selective process
for the uptake of macromolecules
high affinity receptors permit the selective
concentration of ligands from the medium,
minimize the uptake of fluid or soluble
unbound macromolecules, and increase
the rate at which specific molecules enter
the cell
involves clathrin-coated pits
o cell membrane with
invaginations/pits where the
receptors for a particular molecule
can be found
o underneath the pits in the
cytosolic side is a contractile
protein called clathrin
may be a mechanism through which
certain viruses enter the cell causing
diseases
o HIV affects T cells
o Hepatitis liver cells
o Poliomyelitis motor neurons
e.g. LDL receptors cholesterol
Receptors that can recognize
carbohydrate moieties extracellular
glycoproteins
o Galactosyl receptors
asialoglycoproteins
o mannose 6-phosphate moiety
receptors acid hydrolases

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Additional Information about Clathrin

has a three-limbed structure (triskelion)
each limb made of one light and one heavy chain
of clathrin
polymerization of clathrin into a vesicle
o directed by assembly particles composed
of four adapter proteins that interact to the
receptors ensuring the selectivity of
uptake
o involves PIP2 (phosphatidylinositol 4.5bisphospate) for vesicle assembly
o dynamin binds and hydrolyzes GTP for
the pinching off of clathrin-coated vesicles
from the cell surface
Fluid in the ECF

ligand

receptor
pith

invagination

clathrin

phagolysosomes (contain hydrolytic enzymes) which will

digest the contents of the vesicles
digested materials will be converted to amino acids,
simple sugars and nucleotides
transported out of the
vesicles to be used by the cell
What happen to the PM after Endocytosis?
PM getting less and less
*endocytosed large materials in the expense of their PM
have to add phospholipids and proteins OR change the
membrane itself
membrane assembly
2. PINOCYTOSIS
also called cell eating
involves ingestion of large particles: whole
cells (bacteria), particles (viruses) and
cellular debris
involves specialized cells
o macrophages for more and
prolong infection; can engulf an
entire cell
o neutrophils present in CBC; for
acute inflammation
during severe infections, macrophages
ingest a large volume of their cell
membrane through this process
can ingest their whole CM in 30 mins
ingest 25% of their volume per hour

A. Fluid-phase Pinocytosis
formation of invaginations which will become larger until
the two sides of the membrane fuse, sealing the neck of
the PM at the original site of invagination forming a fluidfilled vesicles
B. Absorptive Pinocytosis
formation of invaginations bringing the receptor inside it
for digestion (called internalization)
some receptors are digested like that of insulin receptor
(that is why people consuming too much sweets develop
Type II diabetes); some are returned back to the
membrane like that of LDL receptor
Fate of the vesicles after the invagination
acted upon by lysosomes producing primary
phagolysosomes that will eventually become secondary

internalize 3% of its PM each minute

o leads to membrane assembly
mechanism like that of absorptive
pinocytosis
involves formation of pits
and primary and secondary
phagolysosomes
Can the CM become too thick?
opposite of endocytosis
exocytosis

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II. EXOCYTOSIS
release of macromolecules to the exterior
(products coming from the cell going to the
outside)
from the site of production (ribosomes) that is
attached to the ER
transported to Golgi
apparatus for processing, packaging and
formation of vesicles
o when theres signal, vesicles will fuse with
the PM and extrude its contents outside
signal for initiation is often via a hormone binding
2+
to cell surface receptors
increasing Ca
2+
o Ca triggers exocytosis
Three fates of molecules released thru exocytosis:
1. attach to cell surface to become peripheral
proteins (e.g. antigen)
2. may become a part of extracellular matrix
(collagen, GAGs/glycosaminoglycans)
3. may enter ECF and signal other cells
(hormones and enzymes)

Final sorting of many membrane proteins occur in

the trans golgi
Specific sorting sequences guide proteins to
particular organelles
o (Ex: mannose-6-PO4 guides hydrolases
destined for lysosomes while KDEL [LysAsp-Glu-Leu] specify proteins for the
Endoplasmic Reticulum)
LIPID ASSEMBLY
Enzymes responsible reside in the cisternae of
Endoplasmic Reticulum
Phospholipids self-assemble as they are
synthesized into thermodynamically stable bilayers
Lipid vesicles migrate and fuse with Golgi
Apparatus membrane which in turn fuse with
Plasma Membrane
PROTEIN ASSEMBLY
Explained by the SIGNAL HYPOTHESIS
The signal hypothesis proposes that
proteins destined for secretion, which
involves the movement of the protein
across a biological membrane, are
originally manufactured with an initial
sequence of amino acids that may or
may not present in the mature
protein.

*Exocytosis involves the contact of two inside-surface

(cytoplasmic side) monolayers, whereas endocytosis
results from the contact of two outer-surface monolayers.
MEMBRANE, LIPID AND PROTEIN ASSEMBLY
MEMBRANE ASSEMBLY
Both lipids and proteins are inserted independently
in membranes
Lipids and proteins turnover independently and at
different rates
Topogenic sequences (signal N terminal or
internal or stop) are important in determining the
structure of proteins in membranes

Requires Endoplasmic Reticulum--> Golgi

Apparatus--> Vesicles --> Plasma Membrane
The information for both modes of translocation is
encoded in the protein in the form of a short-lived
sequence extension (signal sequence).
Additional information resides in the ribosome in
the case of co-translational translocation, which
proceeds via a ribosome--membrane junction.
Translocation is mediated by specific receptors
(ribosome and/or signal receptors) which are
restricted in their location to distinct cellular
membranes.

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2 kinds of proteins :
those synthesized by membrane bound ribosomes
(secreted proteins and integral proteins) that
contain a SIGNAL PEPTIDE at their N-terminal
those synthesized by free ribosomes (cytosolic
proteins, extrinsic proteins in the inner Plasma
Membrane leaflet) that lack signal peptide

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