membrane and signal transduction

8/9/2019 Membrane and Signal Transduction

1/22

MEMBRANE AND SIGNAL TRANSDUCTION

A group seminar presentation

Course code: BCH 625

Course: Membrane Biophysics

Presented by;

OKESINA, Akeem Ayodeji (04/46KA046)

ADENIYI, Philip Adeyemi (05/46KA092)

ADEKOMI Damilare Adedayo (04/48KC194)

POPOOLA Niyi Abdulgafar (02/47KA068)

OYEDEPO Kolade Emmanuel (02/47KA063)

Department of Biochemistry, University of Ilorin,

Ilorin, Nigeria.

Lecturer: Dr. R. Arise

July, 2010


2/22

Table of Content

Title Page

Introduction to Membrane

Structure of Membrane Function

Historical Background of Signal Transduction

Signal Transduction

Stages of Cell Signalling

References


3/22

MEMBRANE

INTRODUCTION

The plasma membrane is composed primarily of two types of molecules

lipids, which are fatty or oily molecules, and proteins. The basic structuralframework of the plasma membrane is formed by two sheets of lipids, each

sheet a single molecule thick. Within this double layer, or bilayer, of lipids, the

protein molecules are embedded. Proteins are responsible for a host of

functions, including transporting substances across the membrane, aiding

communication between cells, and carrying out chemical reactions. In most

cells, the plasma membrane is about 40 percent lipid and 60 percent protein, but

these proportions vary greatly, from as little as 20 percent to as much as 75

percent protein depending on the type of cell (Farabee 2007)

STRUCTURE

Most of the lipids in the plasma membrane are of a specific type known as

phospholipids. A phospholipid molecule has a head region at one end that is

hydrophilicit can mix with water. At the other end are two long tails that are

hydrophobicthey do not mix well with water. In the plasma membranes

bilayer construction, phospholipid molecules are arranged so that their

hydrophilic heads point outward on either side of the membrane, and their

hydrophobic tails point toward each other in the middle of the membrane. Thisorientation keeps the hydrophobic tails away from the watery fluids that both

fill and surround living cells. In fact, the plasma membrane stays intact

precisely because the phospholipid molecules strongly resist any change in

configuration that would expose their hydrophobic tails to the watery

environment. (Farabee 2007)

While the phospholipids are held in a bilayer, scientists believe the plasma

membrane as a whole is a fluid structure because phospholipid molecules and

some proteins can move sideways within the membrane. In one second, a singlephospholipid molecule can travel the length of a large bacterial cell. Proteins

drift more slowly through the membrane. With protein molecules scattered

among the phospholipid molecules, the plasma membrane appears to be a

mosaic of phospholipids and proteins. Some of the proteins are found on the

inner or outer surface of the plasma membrane, while others span the membrane

and protrude on either end. Scientists refer to this concept of the plasma

membranes structure as the fluid mosaic model. (Farabee 2007)

The movement of the phospholipid and protein components through the plasma

membrane permits the membrane to change shape. This flexibility is crucial to


4/22

many different types of cells. For example, a single-celled organism known as

an amoeba moves by changing shape, stretching out one part of the cell in the

direction of travel and dragging the rest along behind. Human red blood cells

readily change shape as they squeeze through the bodys smallest blood vessels.

(Farabee 2007)

In animal cells, cholesterol also contributes to the fluidity of the plasma

membrane. Cholesterol is a small lipid molecule that nestles among the

hydrophobic tails of the phospholipids in the interior of the membrane. It

prevents phospholipid molecules from packing together too tightly and making

the membrane rigid. It also acts as an antifreeze for the plasma membrane,

preventing the membrane from freezing to a jellylike consistency at low

temperatures. Plants and fungi have similar molecules that increase the fluidity

of their plasma membranes. (Farabee 2007)

The lipid and protein molecules that make up the plasma membrane are

manufactured inside the cell and routed to the cell surface. The membrane is a

dynamic structure, with molecules constantly being added to and removed from

the plasma membrane as a cell moves and grows. (Farabee 2007)

(www.lookfordiagnosis.com)


5/22

(www.ucl.ac.uk/sjjgsca/cells.)

FUNCTION

1. ALLOW TRANSPORT OF MATERIALS ACROSS IT:

The plasma membrane forms an extremely effective seal around the cell. Only a

very few molecules can pass directly through the lipid bilayer to get from one

side of the membrane to the other. Many substances that a cell needs in order to

survive cannot cross the lipid bilayer on their own, including glucose (a sugar

that cells burn for energy), amino acids (the building blocks of proteins), and

ions, such as sodium and potassium. A cell uses two methods to move such

substances from one side of the plasma membrane to another, known as passivetransport and active transport. Both of these processes involve proteins in the

plasma membrane. (Farabee 2007)

Passive transport is accomplished by diffusion, the spontaneous movement of a

substance from a region of greater concentration to a region of lesser

concentration. The difference between the concentration of a substance in two

different areas is known as a concentration gradient. Diffusion moves

molecules down a concentration gradient in a manner that does not require the

cell to expend energy. Water, oxygen, carbon dioxide, and a few other small


6/22

molecules diffuse directly across the plasma membrane by passing

between(Farabee 2007)

phospholipid molecules. Substances that cannot pass directly through the

plasma membrane diffuse into or out of cells with the aid of hollow, channel-like proteins in a process known as facilitated diffusion. These channel proteins

are shaped so that only one substance, or a small group of closely related

substances, can pass through each type of protein. This specificity enables a cell

to control precisely the molecules that travel in and out of the cell. (Farabee

2007)

In order to move substances against a concentration gradientthat is, from the

side of the plasma membrane where the concentration of a substance is lower to

the side where it is already highera cell must expend energy in a process

known as active transport. Active transport is achieved by membrane proteinscalled pumps, which have a docking site that is shaped to fit a specific

substance. These pumps are open on either the inside or the outside of the cell.

When the proper molecule or ion attaches to the docking site, the pump changes

shape so that the docking site moves its opening to the other side of the plasma

membrane, releasing the molecular cargo. Many pumps obtain the energy

necessary to perform this work from adenosine triphosphate (ATP), a molecule

that serves as the main energy currency of living cells. (Farabee 2007)

Two additional transport mechanisms provide pathways for large molecules topass in and out of cells. In endocytosis, the plasma membrane folds inward,

forming a pouch that traps molecules. The pouch continues to press inward until

it forms a closed sac that breaks loose from the plasma membrane and sinks into

the cell. The second mechanism, exocytosis, is a reversal of endocytosis. A sac

inside the cell containing proteins and other molecules moves toward the outer

edge of the cell until it touches the plasma membrane. The membrane of the sac

then joins with the plasma membrane, and the contents of the sac are released

from the cell. Most of the proteins released by animal cells, such as hormones

and antibodies, exit the cells where they are made through exocytosis. (Farabee2007)

2. COMMUNICATION BETWEEN CELLS:

In multicellular organisms, the plasma membrane also plays a critical role in

communication between cells. Proteins embedded in the plasma membrane act

as receptors, binding to hormones and other molecules sent as signals from

other cells. In animal cells, certain membrane proteins also act as markers that

help the immune system distinguish the bodys own cells from foreign cells.

These marker proteins help trigger the immune reaction that protects humans


7/22

and other animals from disease-causing organisms such as bacteria, viruses, and

fungi. These markers also play a role in the rejection of transplanted tissues and

organs. (Farabee 2007)

3.IT ALSO HELP IN HOLDING THE CELLS TOGETHER:

In certain types of cells, the plasma membrane has a wide variety of additional

functions. Some membrane proteins are involved in holding neighbouring cells

together. (Farabee 2007)

HISTORICAL BACKGROUND OF SIGNAL TRANSDUCTION

Cells from nerves, glands, and other tissues communicate with each other by

releasing hormones or other substances that act as chemical signals. In research

conducted in the 1960s and 1970s, Rodbell of the National Institute of

Environmental Health Sciences had demonstrated that cells bind the cellular

molecule guanosine triphosphate (GTP) to their surfaces. This binding activates

the transduction, or conversion, of the exterior message to an internal message

that then triggers a chemical activity inside the cell. (

"signal transduction." A

Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://www.en

cyclopedia.com/doc/1O6-signaltransduction.html).

Gilman built on Rodbell's work by identifying the protein to which GTP can

bind. Experimenting with mutated leukemia cells, Gilman showed that even

though the cells had all the necessary receptors for transmitting a message from

outside to inside the cell, they were unable to do so. After many years of work,

he and his colleagues isolated a protein that, when added to the cell's membrane,

bound GTP and restored the message-transducing function in the mutated cell.

Because GTP was bound by this protein, Gilman named it the G-protein. Since

Gilman's original discovery, many different types of G-proteins have been

found. The senses of smell, taste, and sight rely on G-proteins to transmit

information along nerve cells. Other G-proteins regulate cell metabolism and

control cell division. (


8/22

"signal transduction." A Dictionary of Biology. 2004. Retrieved July 09, 2010 from

Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Some diseases can alter the functioning of G-proteins. Cholera, for instance,

produces a toxic enzyme that affects the G-proteins present in the cells of the

intestine, interfering with the ability of the cells to absorb water and salt that the

body needs. Left unchecked, this condition leads to rapid dehydration and death.

G-proteins may also play a part in some symptoms associated with diabetes and

alcoholism. Certain genetic disorders can cause cells to have too many or too

few G-proteins, thereby altering cell function in an adverse way. (

"signal

transduction." A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

As well as other honours, Gilman has also received the Albert Lasker Basic

Medical Research Award (1989). Gilman currently chairs the Department of

Pharmacology at the University of Texas Southwest Medical Center in Dallas. (



In the 1940s and 1950s Sutherland studied the hormones epinephrine and

glucagon. Both were known to play a role in releasing glucose (sugar) in the

liver, which the body uses as a source of energy. The exact mechanism of their

action, however, was not understood. In a series of experiments in the 1950s,

Sutherland discovered the molecule cyclic AMP and its role in this process. He

uncovered a chain of chemical reactions that began outside the cell and

continued within it to convert glycogen (stored sugar) to glucose. These

reactions begin when hormones attach, or bind to specific sites on the outside of

a cell membrane. This activates the enzyme (proteins that cause or accelerate

chemical reactions) adenylate cyclase within the cell membrane, which in turn

triggers the release of cyclic AMP within the cell. Cyclic AMP then changes an

inactive enzyme phosphorylase to its active form, which causes glycogen to be

converted to glucose. Sutherland described the hormones in this process as a

first messenger, and cyclic AMP and other intermediates as second messengers.

When he and others found this same reaction in both simple bacteria and

humans, it became clear that this mechanism had been conserved through


9/22

evolution over millions of years. Sutherland studied cyclic AMP thoroughly, as

well as another second-messenger molecule known as guanosine

monophosphate (cyclic GMP). Sutherland's discoveries laid the foundation for

the work of today's biochemists and molecular biologists studying signal

transduction (information relayed to the nucleus of the cell via chemical signals,such as hormones), which has relevance to medical diagnosis, drug

development, and gene therapy. (



Sutherland received many honours for his discoveries. He was elected to the

U.S. National Academy of Sciences in 1966. He won both the GairdnerInternational Foundation Award and the Albert Lasker Basic Medical Research

Award in 1970. (

"signal transduction." A Dictionary of Biology. 2004. Retrieved July 09,

2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-

signaltransduction.html).

SIGNAL TRANSDUCTION

Signal transduction originates at the membrane, where the clustering ofsignalling proteins is a key step in transmitting a message. Membranes are

difficult to study, and their influence on signalling is still only understood at the

most rudimentary level. Recent advances in the biophysics of membranes,

surveyed in this review, have highlighted a variety of phenomena that are likely

to influence signalling activity, such as local composition heterogeneities and

long-range mechanical effects.Signal transductionAnymechanism by which binding of an extracellular signalmolecule to a cell-surface receptor triggers a response

inside the cell.

The mechanism depends on the type of signal molecule (e.g. hormone,

paracrine, or autocrine signals), but it often involves changes in concentration of

a second messenger (e.g. cyclic AMP, calcium ions) within the cell, which in

turn can affect numerous cell activities. Many receptors are associated with G

proteins, which act to turn signal transduction pathways on and off. Other

important components of signal transduction include protein kinases, which

activate enzymes by transferring a phosphate group from ATP (


10/22

"signal

transduction." A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.co

m: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Cells usually communicate by releasing chemical messengers targeted for cells

that may not be immediately adjacent. Some messengers travel only short

distances. Such molecules are called local regulators: a substances that

influences cells in vicinity. E.g. animal growth factors, which are compounds

that stimulate nearby target cells to grow and multiply. Numerous cells can

simultaneously receive and respond to the molecules of growth factors produced

by a single cell in their vicinity. This type of local signalling in animals is called

paracrine signalling.(" A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Enc

yclopedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

Another specialized type of local signalling occurs between nerve cells. One

nerve cell produces a neurotransmitter, that diffuses (across a synapse) to a

single target cell that is touching the first cell. " (A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-


Both animals and plants use chemicals called hormones for signalling at greaterdistances. Cells may also communicate by direct contact. Both animals and

plants have cell junctions that provide cytoplamic continuity between adjacent

cells. Also, animal cells may communicate via direct contact between molecules

on their surfaces. This sort of signalling is important in embryonic development

and in the operation of the immune system. (" A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://www.encyclopedia.com/doc/1O6-



11/22

(" A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.com: http://ww

w.encyclopedia.com/doc/1O6-signaltransduction.html).

STAGES OF CELL SIGNALLING.

From the perspective of the cell receiving the message, cell signalling can be

divided into three stages: Signal reception, Signal transduction, and Cellular

response. When reception occurs at the plasma membrane, the transduction

stage is usually a pathway of several steps, with each molecule in the pathway

bringing about a change in the next. The last molecule in the pathway triggers

the cell's response.( A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclo

pedia.com: http://www.encyclopedia.com/doc/1O6-signaltransduction.html).


12/22

" A Dictionary of Biology . 2004. Retrieved July 09, 2010 from Encyclopedia.com:

http://www.encyclopedia.com/doc/1O6-signaltransduction.html).

SIGNAL RECEPTION AND THE INITIATION OF TRANSDUCTION

A signal molecule binds to a receptor protein, causing the protein to change

shape. A cell targeted by a particular chemical signal has molecules of a

receptor protein that recognizes the signal molecule. The signal molecule is

complementary in shape to a specific site on the receptor and attaches there, like

a key in a lock. The signal molecule behaves as a ligand, the term for a small

molecule that specifically binds to a larger one. Ligand binding causes areceptor protein to undergo a change in conformation, that is a change in shape.

For many receptors, this shape change directly activates the receptor so that it

can interact with another cellular molecule. For other receptors the immediate

effect of the ligand binding causes the aggregation of two or more receptor

molecules. (Gilman, 1987).

MOST SIGNAL RECEPTORS ARE PLASMA-MEMBRANE PROTEINS.

G-Protein-Linked Receptors. This is a plasma-membrane receptor that workswith the help of a protein called a G protein and another protein, usually an


13/22

enzyme. In the absence of the extracellular signal molecule specific for the

receptor, all three proteins are in inactive form. The inactive G protein has a

GDP molecule bound to it. When the signal molecule binds to the receptor

protein, the receptor changes shape in such a way that it binds and activates the

G protein. A molecule of GTP replaces the GDP on the G protein. The active Gprotein (moving freely along the membrane) binds to and activates the enzyme,

which triggers the next step in the pathway leading to the cell's response. The G

protein then catalyzes the hydrolysis of its GTP and dissociates from the

enzyme, becoming available for reuse. All three proteins remain attached to the

plasma membrane. (Gilman, 1987).


14/22

(Gilman, 1987).

Tyrosine-Kinase Receptors. In the absence of specific signal molecules,

tyrosine-kinase receptors exist as single polypeptides in the plasma membrane.

The extracellular portion of the protein, with the signal-molecule binding site, is

connected by a single transmembrane helix to the protein's cytoplasmic portion.

This part of the protein is responsible for the receptor's tyrosine-kinase activityand also has a series of tyrosine amino acids. When signals molecules (such as a


15/22

growth factor) attach to their binding sites, two polypeptides aggregate, forming

a dimer. Using phosphate groups from ATP, the tyrosin-kinase region of each

polypeptide phosphorylates the tyrosines on the other polypeptide. In other

words, the dimer is both an enzyme and its own substrate. Now fully activated,

the receptor protein can bind specific intracellular proteins, which attach toparticular phosphorylated tyrosines and are themselves activated. Each can then

initiate a signal-transduction pathway leading to a specific cellular response.

Tyrsine-kinase receptors often activate several different signal-tranduction

pathways at once, helping regulate such complicated functions as cell

reproduction (cell divisions). Inappropriate activation of these receptors can

lead to uncontrolled cell growth - cancer.(Li and Hristova 2006)

(Li and Hristova 2006)


16/22

Ion-Channel Receptors. Some membrane receptors of chemical signals are

Ligand-gated ion channels. These channels are protein pores in the plasma

membrane that open or close in response to the binding of a chemical signal,

allowing or blocking the flow of specific ions, such as Na+ or Ca2+ into the cell.

Often the change in the concentration of a particular ion inside the cell directlyaffects cell function. (Hille, 2001).

(Hille, 2001).

Intracellular Receptors. Not all signal receptors are membrane proteins. Some

are proteins located in the cytoplasm or nucleus of target sells. To reach such areceptor, a chemical messenger must be able to pass through the target cell's


17/22

plasma membrane. A number of important signaling molecules can do just that,

either because they are small enough to pass between the membrane

phospholipids or because they are themselves lipids and therefore soluble in the

membrane. (Albert et al2002)

Signal-Transduction Pathways

The transduction stage of cell signalling is usually a multistep pathway. One

benefit of such a pathway is signal amplification. If some of the molecules in a

pathway transmit the signal to multiple molecules of the next component in the

series, the result can be a large number of activated molecules at the end of the

pathway. That is a very small number of extracellular signal molecules can

produce a major cellular response. (Schlessinger, 1988)

Pathways relay signals from receptors to cellular responses. Like falling

dominoes, the signal-activated receptor activates another protein, which

activates another molecule, and so on, until the protein that produces the final

cellular response is activated. The molecules that relay a signal from the

receptor to response, sometimes called relay molecules, are mostly proteins.

(Schlessinger, 1988)

Protein phosphorylation, a common mode of regulation in cells, is a major

mechanism of signal transduction. A signalling pathway begins when a signal

molecule binds to a membrane receptor. The receptor then activates a relay

molecule, which activates a protein kinase (1). Active protein kinase 1 transfers

a phosphate from ATP to an inactive molecule of another protein kinase

molecule (2), thus activating this second kinase. In turn, active protein kinase 2

catalyzes the phosphoralation (and activation) of protein kinase 3. Finally,

active protein kinase 3 phosphorylates a protein that brings about the cell's final

response to the signal. Each activated protein kinase molecule is inactivated bythe removal of tha phosphate group by enzymes called phosphatases. This make

the protein kinases available for reuse. (Schlessinger, 1988)


18/22

(Schlessinger, 1988)

Second Messengers

Certain small molecules and ions are key components of signaling pathways

(second messengers). The extra cellular signal molecule that binds to the

membrane receptor is a pathway's "first messenger". Because second

messengers are both small and water-soluble, they can readily spread

throughout the cell by diffusion. Second messangers participate in pathwaysinitiated by both G-protein-linked receptors and tyrosine-kinase receptors. The

two most widely used second messengers are cyclic AMP and calcium ions,

Ca2+. A large variety of relay proteins are sensitive to the cytosolic

concentration of one or the other of these second messengers. (Hanna et al

1984)

Cyclic AMP (cAMP) Cyclic AMP is a component of many G-protein-signaling

pathways. The signal molecule - the "first messanger" - activates a G-protein-

linked receptor, which activates a specific G protein. In turn, the G protein


19/22

activates adenylyl cyclase, which catalyzes the conversion of ATP to cAMP.

(Hanna et al1984).

(Hanna et al1984)

Calcium Ions and Indositol Triphosphate Calcium ions (Ca2+) are actively

transported out of the cytosol by a variety of protein pumps. Pumps in the

plasma membrane move Ca2+ into the extracellular fluid, and ones in the ER

membrane Ca2+ into the lumen of the ER. Consequently, the Ca2+ consentration

in the cytosol is usually muth lower than in the extracellular fluid and ER.

Additional Ca2+ pumps in the mitochondrial inner membrane operate when the

calcium level in the cytosol rises significantly. These pumps are driven by the

proton-motive force generated across the membrane by mitochondrial electrontransport chains. Calcium ions (Ca2+) and indositol trisphosphate (IP3) functions

as second messengers in many signal-transduction pathways. The process is

initiated by thebinding of a signal molecule to either a G-linjed receptor or a

Tyrosine-kinase receptor. In The following figure the circled numbers trace the

former pathway. 1- Asignal molecule binds to a receptor, leading to 2-

activation of an enzyme celled phospholipase C. 3- This enzyme cleaves a

plasma-membrane phospholipid called PIP2 into DAG and IP3. Both can

function as second messangers. 4- IP#, a small molecule, quickly diffuses

through the cytosol and binds to a ligand-gated calcium channel in the ERmembrane, causing it to open. 5- Calcium ions flow out of the ER (down their


20/22

gradient), raising the Ca2+ level in the cytosol. 6- The calcium ions activate the

next protein in one or more signaling pathways, often acting via calmodulin,

aubiquitous Ca2+-binding protein. DAG functions as a second mesanger in still

other pathways. (Hanna et al1984)

(Hanna et al1984)

Cellular Response to Signals

Ultimateley, a signal-transduction pathway leads to the regulation of one or

more cellular activities. The regulated activities may occur in the cytoplasm,

such as a rearrangment of the cytoskeleton, the opening or closing of an ionchannel in the plasma membrane, or some aspect of cell metabolism. Many

other signaling pathways ultimately regulate not the activity of an enzyme but

thesynthesis of enzymes or other proteins, usually by turing specific genes on

or off. (King et al2003)


21/22

(King et al2003)


22/22

REFERENCES

1. (www.lookfordiagnosis.com)

2. (www.ucl.ac.uk/sjjgsca/cells.)

3. Alberts B, Lewis J, Raff M, Roberts K, Walter P (2002). Molecularbiology of the cell (4th ed.). New York: Garland Science. ISBN0-8153-

3218-1.

4. Farabee M .J 2007 the fluid mosaic model of the structure of cell

membrane.

5. Gilman A.G. (1987). "G Proteins: Transducers of Receptor-Generated

Signals". Annual Review of Biochemistry 56: 615649.

doi:10.1146/annurev.bi.56.070187.003151. PMID3113327.

6. Hanna MH, Nowicki JJ and Fatone MA (1984). "Extracellular cyclic

AMP (cAMP) during development of the cellular slime mold

Polysphondylium violaceum: comparison of accumulation in the wild

type and an aggregation-defective mutant". J Bacteriol 157 (2): 345349.

PMID215252.

7. Hille B. (2001). Ion channels of excitable membranes. Sunderland, Mass..

ISBN0878933212.

8. King N, Hittinger CT, Carroll SB (2003). "Evolution of key cell signaling

and adhesion protein families predates animal origins". Science 301

(5631): 3613. doi:10.1126/science.1083853. PMID12869759.

9. Li E, Hristova K (2006). "Role of receptor tyrosine kinase

transmembrane domains in cell signaling and human pathologies".

Biochemistry 45 (20): 624151. doi:10.1021/bi060609y.

10.Schlessinger, J. (1988). "Signal transduction by allosteric receptor

oligomerization.". Trends Biochem Sci 13 (11): 4437.doi:10.1016/0968-0004(88)90219-8. PMID3075366.
http://en.wikipedia.org/wiki/International_Standard_Book_Numberhttp://en.wikipedia.org/wiki/Special:BookSources/0-8153-3218-1http://en.wikipedia.org/wiki/Special:BookSources/0-8153-3218-1http://wiki/Digital_object_identifierhttp://dx.doi.org/10.1146%2Fannurev.bi.56.070187.003151http://wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/3113327http://en.wikipedia.org/wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/215252http://wiki/International_Standard_Book_Numberhttp://wiki/Special:BookSources/0878933212http://wiki/Digital_object_identifierhttp://dx.doi.org/10.1126%2Fscience.1083853http://wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/12869759http://en.wikipedia.org/wiki/Digital_object_identifierhttp://dx.doi.org/10.1021%2Fbi060609yhttp://en.wikipedia.org/wiki/Digital_object_identifierhttp://dx.doi.org/10.1016%2F0968-0004(88)90219-8http://en.wikipedia.org/wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/3075366http://en.wikipedia.org/wiki/International_Standard_Book_Numberhttp://en.wikipedia.org/wiki/Special:BookSources/0-8153-3218-1http://en.wikipedia.org/wiki/Special:BookSources/0-8153-3218-1http://wiki/Digital_object_identifierhttp://dx.doi.org/10.1146%2Fannurev.bi.56.070187.003151http://wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/3113327http://en.wikipedia.org/wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/215252http://wiki/International_Standard_Book_Numberhttp://wiki/Special:BookSources/0878933212http://wiki/Digital_object_identifierhttp://dx.doi.org/10.1126%2Fscience.1083853http://wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/12869759http://en.wikipedia.org/wiki/Digital_object_identifierhttp://dx.doi.org/10.1021%2Fbi060609yhttp://en.wikipedia.org/wiki/Digital_object_identifierhttp://dx.doi.org/10.1016%2F0968-0004(88)90219-8http://en.wikipedia.org/wiki/PubMed_Identifierhttp://www.ncbi.nlm.nih.gov/pubmed/3075366

membrane and signal transduction

Documents