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June 18, 2015

CELL MEMBRANE

Susan
C. Tengco, MD, MBA

TOPIC OUTLINE
I. Cell Membrane


a. Cell Membrane Assymetry

b. Functions on Cell Membrane

II. Two Major Body Components

a. Intracellular Fluid Compartment

b. Extracellular Fluid Compartment

III.
Composition of Cell Membrane

a. Lipids

i. Types of Lipids

b. Proteins


i. Types of Membrane Proteins

c. Carbohydrates

IV. Fluid-Mosaic Model

a. Factor Affecting Membrane Fluidity

i. Importance of Increased Membrane

Fluidity

V.
Artificial
Membranes and Other Special

Membrane
Structures

a. Micelles


b. Liposomes

c. Tight Junctions

d. Gap Junctions

VI. Signal Transduction

VII. The Cell Membrane and Transport Systems

a. Transport Systems

b. Cross Membrane Transport of Small

Molecules

i. Passive Transport


ii. Carrier Mediated Transport

iii. Osmosis

c. Cellular Transport of Macromolecules

i. Endocytosis

- Pinocytosis

- Phagocytosis

ii.
Exocytosis

VIII.Membrane Assembly

IX. Lipid Assembly


X. Protein Assembly

CELL MEMBRANE

Asymmetric, sheet-like structure with an inner leaflet

(exposed to the ICF) and an outer one (exposed to the
ECF)
Exists in viscousgel-fluid likeand plastic
structures (ex. RBCs).
Dynamicexhibits rapid turnover and lateral
diffusion
Has a thermodynamically stable and metabolically
active arrangement

Composed of lipids, proteins, and carbohydrates

A. Cell Membrane Assymetry
INSIDE-OUTSIDE ASYMMETRY
o Due to the irregular distribution of proteins
o Carbohydrates are only found externally
o Specific locations of enzymes (ex. In the
mitochondria, enzymes involved in ETC are found
on the inner mitochondrial membrane)
o Nature of phospholipids
Outer leaflet: phosphatidylcholine,
sphingomyelin, glycolipids
Inner leaflet: phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol
REGIONAL ASYMMETRY
o Villous borders, gap junctions, tight junctions
o Can only be found in specific sites

B. Functions of Cell Membrane
Selective barrier - aided by carriers and channels,
allowing exchange between the cell and the
environment
Permits cell individuality separates cell from other
cells
Cell-to-cell interaction due to hormone-receptor
interactions
Cell adhesion to basement membrane and other cells
Transmembrane signaling signal transduction
mechanism
Compartmentalization
Localize enzymes
Excitation-response coupling
Site for energy transduction

Disruption of the cell membrane results to diseases:

1. Familial hypercholesterolemia

Lipids not
directly
absorbed by
cells

Bind to
proteins
(LDL) to be
absorbed

Premature
atherosclerosis

1 of 8 Cell Membrane [Maki, Mayo, Maago, Mendoza, Morales]

LDL
receptors
lacking in
cell
membrane

LDLs stay in
the blood
vessles and
accumualate

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Cell Membrane

2. Congenital Goiter

Iodine needs
receptors to be
absorbed into
cells

Cell membrane
lacks Iodine
receptors

Thyroid
hormones are
not produced

Iodine is not
absorbed

3. Myocardial Ischemia
4. Acute Pancreatitis

Pancreas make
and keep
digestive
enzymes in
inactive state

Injlammation
of pancreas

Cell
membrane is
disrupted

Digestion of
nearby
structures
will occur

Enzymes will
leak out

TWO MAJOR BODY COMPONENTS

A. INTRACELLULAR FLUID COMPARTMENT (ICF)
o 2/3 (40%)of total body water
o Provides proper environment for cell to:
Synthesize, store and utilize energy
Repair itself
Replicate
Perform special function
o Cell housekeeping function
o Predominant ions: K+, Mg2+, PO4-, proteins;
negatively charged

B. EXTRACELLULAR FLUID COMPARTMENT (ECF)
o 1/3 (20%) of total body water
o Subdivided into plasma and interstitial fluid
o Acts as transport/delivery system of nutrients,
ions, oxygen, hormonesand waste products
o Predominant ions: Na+, Ca2+, Cl-, glucose

Notes:
The ICF and ECF have different compositions and
consistencies
Changes in the composition occur from time-to-time,
but will return to normal due to membrane activity

COMPOSITION OF CELL MEMBRANE

A. LIPIDS
Provide basic structure; backbone
Amphipathic due to hydrophobic and hydrophilic
parts attributing to formation of a bilayer
With FA tails
o Saturated FAs straight tailsorganized,
compact, crystalline membrane
o Unsaturated FAs kinked tailsdue to double
bond, disorganized, fluid membrane

Three Important Types of Lipids
1. Phospholipids lipids with Phosphate groups. Lends
to selective permeability of cell membrane as it allows
lipophilic substances (e.g O2, CO2, alcohol) to pass
through.
Polar head group

Apolar, hydrocarbon tails

Figure 1. Phospholipids

Aqueous
Hydrophilic

Hydrophobic

Hydrophilic
Aqueous
Figure 2. Lipid Bilayer

i. Phosphoglycerides
-
most common phospholipid
-
consist of a glycerol backbone + 2 fatty acid
chains connected via ester linkages +
phosphorylated alcohol
-
(e.g. ethanolamine, choline, serine, glycerol,
or inositol)
-
Fatty acids are even-numbered (16-18 C
atoms) which could be saturated or
unsaturated

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Cell Membrane

Simplest phosphoglyceride is phosphatidic

acid

-
-
-

All parts are hydrophobic except for the

hydroxyl group near the polar heads.
Moderator molecule that moderates
membrane fluidity
Increases fluidity if T < Tm*
Decreases fluidity if T > Tm

*Tm transition temperature; temperature at which cell
membrane becomes disorganized

Figure 3. Phosphoglyceride

ii. Sphingomyelin

Figure 5. Cholesterol

B.

Legend:
Phosphorylcholine
Sphingosine
Fatty Acid

Figure 4. Sphingomyelin

-
-
-

-
-

second major class of phospholipid

contains a sphingosine backbone instead of
glycerol
A fatty acid is attached by an amide link to
the amino group of sphingosine =
CERAMIDE
Hydroxyl group of sphingosine is esterified
to phosphorylcholine
Sphingomyelin is prominent in myelin
sheath

2. Glycosphingolipids sugar attached to a ceramide
backbone; found in nerve tissues
i. Cerebrosides
ii. Gangliosides

3. Sterols
i. Cholesterol
-
Most common sterol and intercalates with
membrane phospholipids
-
27-Carbon atom with 4 rings conferring
rigidity

PROTEINS
Amphipathic structures
Determines membrane function
Act as pumps, channels, carriers, receptors, enzymes,
structural components, antigens

Two Types of Membrane Proteins
1. Integral/Transmembrane
-
attached directly to phospholipids
-
require detergents to be removed
-
amphipathic, globular and spans the bilayer
(transmembrane) several times in certain
proteins
-
asymmetrically distributed in cell membrane

2. Peripheral
-
do not interact directly with phospholipids
-
attached to integral proteins
-
usually found inside the cell
-
Some are cytoskeletal proteins (ex. Ankyrin in
RBCs is attached to integral protein Band 3 and
anchors spectrin providing stability to RBCs)

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C.

CARBOHYDRATES
occur in association with lipids or proteins :
glycolipids or glycoproteins
mostly found on the external membrane surface
functions :
o receptors
o antigens
o confers negative charge to cell (as glycocalyx)

FLUID-MOSAIC MODEL (Singer & Nicholson)

Cell Membrane
-

at temperatures below Tm, it INCREASES

FLUIDITY by interfering with the interactions of
hydrocarbon tails of fatty acids (induces disorder)

Importance of Increased Membrane Fluidity

Permeability to water and other hydrophilic molecule
increases
2. Lateral mobility of integral proteins increases*
* especially important with proteins involved in transport
and receptor proteins
3. Increased protein diffusion since some proteins are
internalized, allows for faster appearance

1.

ARTIFICIAL MEMBRANES AND OTHER SPECIAL

MEMBRANE STRUCTURES

A. Micelle

universally accepted description of membrane
structure
icebergs (proteins) floating in a sea of
phospholipids
membranes undergo phasic changes from stiff (gel or
crystalline) to fluid state
both lipids and proteins undergo "rapid
redistribution" in the plane of the membrane ("lateral
diffusion")

Factors Affecting Membrane Fluidity
1. Lipid composition
-
longer and more saturated fatty acid chains
exhibit higher transition temperature
-
unsaturated cis bonds tend to increase membrane
fluidity
-
presence of cholesterol the moderator molecule

2. Temperature
Transition Temperature (Tm) - temperature at
which structure undergoes transition from ordered to
disordered state
-
temperatures = membrane fluidity increases
-
temperatures = hydrophobic side chains
become aligned = stiff structure

3. Role of Cholesterol
- modifies membrane fluidity
- at temperatures above Tm, its rigid structure
LIMITS FLUIDITY (condensing effect)

are relatively small aggregates of amphipathic
molecules forming a monolayer with :
o hydrophobic regions - shielded from H20
o hydrophilic regions - immersed or interact with
H20
arrangement of different regions depends on the
chemical environment where the micelle is situated
single-layer unlike cell membrane
used in detergents
clinical application of micelles :
o are formed when bile acids (which are
amphipathic) associate with products of lipid
digestion
o bile acids-formed micelles assist in the digestion
and absorption of fat plus ADEK

B. Liposomes
Vesicles surrounded with lipid bilayer
Consist of phospholipids that are of natural or
synthetic origin
Lipid content can be varied allowing for examination
of varying lipid composition on certain functions (ie.,
transport)
In the study of factors that affect protein and enzyme
function
May be used for specific drug delivery and gene
therapy

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Cell Membrane

Considered as possible cancer treatment;

manufacturing of lyposomes that deliver drugs
specifically to tumor cells

Tight Junctions
Located below the apical surface of epithelial cells
Prevents the diffusion of macromolecules between
them
Composed of proteins occludin, claudins
Sites of paracellular transport
Means of attachment
Prevents diffusion of macromolecules
Allows paracellular transport of water (e.g. Na+ K+
ATPase)
Physical connection between cells

C.

E.

Low resistance connection between cells

More functional connection
Made of connexons (made of connexins) and are
aligned with another cell
Transports small ions, molecules, and impulses
In heart muscles, they are known as syncytium

Lipid Raft
are dynamic areas of the exoplasmic leaflet of the lipid
bilayer enriched in cholesterol, sphingolipids and
proteins
involved in and enhances signal transduction by
clustering elements of the signaling systems

SIGNAL TRANSDUCTION
biochemical signals from hormones,
neurotransmitters bind to receptors in the cell
membrane
transmits information to the cytoplasm via these
membranes through the generation of signalling
molecules : cyclic nucleotides, calcium, diacylglycerol
and phosphoinositides
Hormones and neurotransmitters cannot enter the
cell, and thus only attach to receptors found in the cell
membrane
Requires secondary messengers (e.g. cAMP, IP3)

D. Gap Junctions

One hormonemultiple effectssignal is amplified

Signal transduction will end once GTP is hydrolyzed
back to GDP

THE CELL MEMBRANE AND TRANSPORT SYSTEMS

Cell membrane transport systems are very important

because :
1. The cell membrane is SELECTIVE
2. Cell membrane RECEIVES AND TRANSMITS
SIGNALS from other cells and chemicals

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Transport Systems

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According to direction of movement:

Cell Membrane

o
o

UNIPORT - moves ONE TYPE of substance
bidirectionally
COTRANSPORT
SYMPORT - moves TWO solutes in the SAME
DIRECTION
Ex: Na+ and glucose cotransport
ANTIPORT - moves TWO solutes in the
OPPOSITE DIRECTION
Ex : Na+ (in) and Ca++ or H+ (out)

Cross Membrane Transport of Small Molecules

A. Passive Transport
SIMPLE DIFFUSION

ION CHANNELS
o are for water soluble substances (ions) that
cannot just simply permeate the membrane
o permeability depends upon size, extent of
hydration and charge density of the ion
o there are specific channels for each ion
o activity of some channels are regulated by
neurotransmitters
o function can be impaired by disease/mutations
o channels can be gated
o ION CHANNEL GATING
VOLTAGE GATING
- channels open or close in response to
changes in membrane potential
- Ex: sodium channels
LIGAND GATING
- a specific molecule or chemical binds to a
receptor which opens the channel
- Ex: binding of Acetylcholine (Ach) to its
receptor opens Na+ channels

AQUAPORINS
o water channels found in certain cells : RBC, distal
tubules and collecting ducts of renal nephrons
o are tetrameric membrane proteins
o 5 distinct aquaporins : AP-1 to AP-5
o mutation in AP-2 is the cause of nephrogenic
Diabetes Insipidus

B. Carrier-Mediated Transport
FACILITATED DIFFUSION

o
o
o

From high to low concentration
No energy required; depends on natural kinetic
energy of molecules
Limited by (1) thermal agitation of molecules, (2)
concentration and electrical gradient, and (3)
solubility of solute
FACTORS AFFECTING SIMPLE DIFFUSION:
1. concentration gradient across membrane
2. electrical potential across membrane
3. permeability coefficient of the substance to the
membrane,, lipid solubility
4. pressure difference across membrane
5. thickness of membrane
6. temperature
7. distance
8. number of channels

o
o
o

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Unilateral transport
Uses a ping-pong mechanism wherein the
carrier undergoes conformational changes
Pong state = carrier is exposed to high
concentrations of solute

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o
o
o

Cell Membrane

Ping state = carrier is exposed to a lower
concentration of solute
Will only work if carrier is available
FACTORS AFFECTING FACILITATED DIFFUSION:
1. concentration gradient across membrane
2. amount of carrier available (key control step)
3. rapidity of solute-carrier interaction
4. rapidity of conformational change for both the
loaded and unloaded carrier
5. presence of certain hormones : Insulin, GH and
glucocorticoids

ACTIVE TRANSPORT
o transport is away from thermodynamic
equilibrium (energy requiring)
o Two types:
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

Secondary Active Transport

Ex. Gluc-Na+ transport will only occur

after action of Na+K+ATPase
Primary mechanism of oral rehydration
solutions

Legend:
- Primary Active Transport
- Secondary Active Transport


C. Osmosis

Energy is supplied by a concentration
gradient caused by action of primary
transport

Net flow of solvent from low solute to high solute
concentration
Requires a semi-permeable membrane with respect to
the solvent
High [solute] = High Osmotic Pressure

OSMOTIC PRESSURE
o minimum pressure required to negate or reverse
osmosis.
o 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

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Cell Membrane

Cellular Transport of Macromolecules

A. Endocytosis
uptake of proteins, polysaccharides, and
polynucleotides

PINOCYTOSIS

B. Exocytosis
is the release of macromolecules to the exterior
signal for initiation is often via a hormone which binds
to cell-surface receptors increased Ca++
3 fates of molecules released thru exocytosis :
o attach to cell surface to become peripheral
proteins (Ex: antigens)
o may become part of extracellular matrix (Collagen,
GAGs)
o may enter ECF and signal other cells (hormones)

EXOCYTOSIS VS. ENDOCYTOSIS

MEMBRANE ASSEMBLY

A. Fluid-Phase Pinocytosis
o nonselective
o uptake through small vesicles
o active process
B. Absorptive Pinocytosis
o selective; receptor-mediated
o involves clathrin-coated pits which require Ca to
contract.
o Ex: LDL Receptors

*Downregulation internalization of receptors via
absorptive pinocytosis. Occurs when there is continuous
exposure of receptors to ligands.

PHAGOCYTOSIS
involves ingestion of large particles : whole cells
(bacteria), particles (viruses) and cellular debris
involves only specialized cells : macrophages and
neutrophils
macrophages ingest a large volume of their cell
membrane through this process

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
final sorting of many membrane proteins occur in the
trans golgi
specific sorting sequences guide proteins to particular
organelles (Ex: mannose-6-PO4 guides hydrolases
destined for lysosomes while KDEL [Lys-Asp-Glu-Leu]
specify proteins for the ER)

LIPID ASSEMBLY

enzymes responsible reside in the cisternae of ER

phospholipids self assemble as they are synthesized
into thermodynamically stable bilayers
lipid vesicles migrate and fuse with GA membrane
which in turn fuse with PM

PROTEIN ASSEMBLY

explained by the SIGNAL HYPOTHESIS

requires ER--> GA--> --> PM
there are 2 kinds of proteins :
o those synthesized by membrane bound
ribosomes (secreted proteins and integral
proteins) that contain a SIGNAL PEPTIDE at their
N-terminal
o those synthesized by free ribosomes (cytosolic
proteins, extrinsic proteins in the inner PM leaflet)
that lack signal peptide

Aim high and always hit the best.

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