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Cell signalling

By:

Khuram Aziz

M.phill biochemiatry


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Cellular Signaling

Many living organisms contain billions of cells

that carry out diverse functions. In order for the

cells to cooperate, cells need to be able to

communicate with each other. Many of the

genes that cells are capable of synthesizing are

thought to be involved in cellular signaling.


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Environmental stimuli

With single-celled organisms, the variety of signal

transduction processes influence its reaction to its

environment.

With multicellular organisms, numerous processes arerequired for coordinating individual cells to support the

organism as a whole; the complexity of these processes

tend to increase with the complexity of the organism.

Sensingof environments at the cellular level relies onsignal transduction; many disease processes, such

as diabetes and heart disease arise from defects in these

pathways, highlighting the importance of this process in

biology and medicine.
http://en.wikipedia.org/wiki/Single-celled_organismhttp://en.wikipedia.org/wiki/Multicellular_organismshttp://en.wikipedia.org/wiki/Sensehttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Atherosclerosishttp://en.wikipedia.org/wiki/Atherosclerosishttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Sensehttp://en.wikipedia.org/wiki/Multicellular_organismshttp://en.wikipedia.org/wiki/Multicellular_organismshttp://en.wikipedia.org/wiki/Multicellular_organismshttp://en.wikipedia.org/wiki/Single-celled_organismhttp://en.wikipedia.org/wiki/Single-celled_organismhttp://en.wikipedia.org/wiki/Single-celled_organism


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Various environmental stimuli exist that initiate

signal transmission processes in multicellular

organisms; examples include photons hitting

cells in the retina of the

eye, and odorantsbinding to odorant

receptors in the nasal epithelium. Certain

microbial molecules, such asviral nucleotides and protein antigens, can elicit

an immune system response against

invadingpathogens mediated by signal
http://en.wikipedia.org/wiki/Photonhttp://en.wikipedia.org/wiki/Retinahttp://en.wikipedia.org/wiki/Odoranthttp://en.wikipedia.org/wiki/Olfactory_receptor_neuronhttp://en.wikipedia.org/wiki/Olfactory_receptor_neuronhttp://en.wikipedia.org/wiki/Olfactory_epitheliumhttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Olfactory_epitheliumhttp://en.wikipedia.org/wiki/Olfactory_receptor_neuronhttp://en.wikipedia.org/wiki/Olfactory_receptor_neuronhttp://en.wikipedia.org/wiki/Odoranthttp://en.wikipedia.org/wiki/Retinahttp://en.wikipedia.org/wiki/Photon


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Types of cellular signaling

Extra cellular signaling or chemical signaling

Cells direct signaling or intracellular signalling


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Ectracellular signaling

signaling by extracellular, secreted molecules can

be classified into three typesendocrine,paracrine, or autocrinebased on the distanceover which the signal acts.


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In endocrine signaling, signaling molecules,

called hormones, act on target cells distant from

their site of synthesis by cells of endocrine

organs. In animals, an endocrine hormoneusually is carried by the blood from its site of

release to its target.
http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7569/http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7569/


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Inparacrine signaling, the signaling molecules

released by a cell only affect target cells in close

proximity to it. The conduction of an electric

impulse from one nerve cell to another or froma nerve cell to a muscle cell (inducing or

inhibiting muscle contraction) occurs via

paracrine signaling.


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autocrine signaling,

cells respond to substances that they themselves

release. Manygrowth factors act in this fashion,

and cultured cells often secrete growth factors

that stimulate their own growth andproliferation. This type of signaling is

particularly common in tumor cells, many of

which overproduce and release growth factorsthat stimulate inappropriate, unregulated

proliferation of themselves as well as adjacent

nontumor cells; this process may lead to
http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7545/http://www.ncbi.nlm.nih.gov/books/n/mcb/A7315/def-item/A7545/


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Cell direct contact signalling

Three types

Gap junctions

Surface protein interactions Receptors


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Receptors

In biochemistry, a receptor is a molecule found on the

surface of a cell, which receives specific chemical

signals from neighbouring cells or the wider

environment within an organism. These signals tell acell to do somethingfor example to divide or die, or

to allow certain molecules to enter or exit the cell.

Receptors are protein molecules, embedded in either

the plasma membrane (cell surface receptors) orthe cytoplasm (nuclear receptors) of a cell, to which one

or more specific kinds ofsignalingmolecules may

attach.
http://en.wikipedia.org/wiki/Biochemistryhttp://en.wikipedia.org/wiki/Moleculehttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Plasma_membranehttp://en.wikipedia.org/wiki/Cell_surface_receptorhttp://en.wikipedia.org/wiki/Cytoplasmhttp://en.wikipedia.org/wiki/Nuclear_receptorhttp://en.wikipedia.org/wiki/Signal_transductionhttp://en.wikipedia.org/wiki/Signal_transductionhttp://en.wikipedia.org/wiki/Nuclear_receptorhttp://en.wikipedia.org/wiki/Cytoplasmhttp://en.wikipedia.org/wiki/Cell_surface_receptorhttp://en.wikipedia.org/wiki/Plasma_membranehttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Moleculehttp://en.wikipedia.org/wiki/Biochemistry


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A molecule which binds (attaches) to a receptor

is called a ligand, and may be a peptide (short

protein) or other small molecule, such as

aneurotransmitter, a hormone, a pharmaceuticaldrug, or a toxin. Each kind of receptor can bind

only certain ligand shapes. Each cell typically has

many receptors, of many different kinds. Simplyput, a receptor functions as a keyhole that opens

a biochemical pathway when the proper ligand is

inserted.
http://en.wikipedia.org/wiki/Ligand_(biochemistry)http://en.wikipedia.org/wiki/Peptidehttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Hormonehttp://en.wikipedia.org/wiki/Hormonehttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Peptidehttp://en.wikipedia.org/wiki/Ligand_(biochemistry)


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Structure

The shapes and actions of receptors are studied

byX-ray crystallography, dual polarisation

interferometry, computer modelling, and

structure-function studies, which have advancedthe understanding ofdrug action at the binding

sites of receptors. Structure activity relationships

correlate induced conformational changes withbiomolecular activity, and are studied using

dynamic techniques such as circular

dichroism and dual polarisation interferometry.
http://en.wikipedia.org/wiki/X-ray_crystallographyhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Computer_simulationhttp://en.wikipedia.org/wiki/Drug_actionhttp://en.wikipedia.org/wiki/Circular_dichroismhttp://en.wikipedia.org/wiki/Circular_dichroismhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Circular_dichroismhttp://en.wikipedia.org/wiki/Circular_dichroismhttp://en.wikipedia.org/wiki/Drug_actionhttp://en.wikipedia.org/wiki/Computer_simulationhttp://en.wikipedia.org/wiki/Computer_simulationhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/Dual_polarisation_interferometryhttp://en.wikipedia.org/wiki/X-ray_crystallographyhttp://en.wikipedia.org/wiki/X-ray_crystallographyhttp://en.wikipedia.org/wiki/X-ray_crystallography


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Binding and activation

Ligand binding is an equilibrium process.

Ligands bind to receptors and dissociate from

them according to the law of mass action.

One measure of how well a molecule fits a

receptor is the binding affinity, which is

inversely related to the dissociation constantKd.

A good fit corresponds with high affinity andlowKd. The final biological response

(e.g. second messenger cascade, muscle

contraction), is only achieved after a significant
http://en.wikipedia.org/wiki/Chemical_equilibriumhttp://en.wikipedia.org/wiki/Law_of_mass_actionhttp://en.wikipedia.org/wiki/Dissociation_constanthttp://en.wikipedia.org/wiki/Second_messenger_systemhttp://en.wikipedia.org/wiki/Second_messenger_systemhttp://en.wikipedia.org/wiki/Dissociation_constanthttp://en.wikipedia.org/wiki/Law_of_mass_actionhttp://en.wikipedia.org/wiki/Chemical_equilibrium


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The receptor-ligand affinity is greater than

enzyme-substrate affinity.Whilst both

interactions are specific and reversible, there is

no chemical modification of the ligand as seenwith the substrate upon binding to its enzyme.


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Constitutive activity

A receptor which is capable of producing its biological

response in the absence of a bound ligand is said to

display "constitutive activity".The constitutive activity

of receptors may be blocked byinverse agonist binding.Mutations in receptors that result in increased

constitutive activity underlie some inherited diseases,

such as precocious puberty (due to mutations in

luteinizing hormone receptors) and hyperthyroidism(due to mutations in thyroid-stimulating hormone

receptors).
http://en.wikipedia.org/wiki/Inverse_agonisthttp://en.wikipedia.org/wiki/Inverse_agonist


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Ligands

(Full) agonistsare able to activate the receptor and result

in a maximal biological response. Most natural ligands

are full agonists.

Partial agonistsdo not activate receptors thoroughly,causing responses which are partial compared to those

of full agonists.

Antagonistsbind to receptors but do not activate them.

This results in receptor blockage, inhibiting the binding

of other agonists.

Inverse agonistsreduce the activity of receptors by

inhibiting their constitutive activity.
http://en.wikipedia.org/wiki/Agonisthttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Agonist


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Cell surface receptor

Cell surface receptors (membrane

receptors, transmembrane receptors) are

specialized integral membrane proteins that take

part in communication between the cell and theoutside world. Extracellular signaling

molecules (usuallyhormones,neurotransmitters,

cytokines, growth factors or cell recognitionmolecules) attach to the receptor, triggering

changes in the function of the cell. This process

is called signal transduction:
http://en.wikipedia.org/wiki/Integral_membrane_proteinhttp://en.wikipedia.org/wiki/Signaling_moleculehttp://en.wikipedia.org/wiki/Signaling_moleculehttp://en.wikipedia.org/wiki/Hormonehttp://en.wikipedia.org/wiki/Neurotransmittershttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Growth_factorshttp://en.wikipedia.org/wiki/Cell_adhesion_moleculehttp://en.wikipedia.org/wiki/Cell_adhesion_moleculehttp://en.wikipedia.org/wiki/Receptor_(biochemistry)http://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Signal_transductionhttp://en.wikipedia.org/wiki/Signal_transductionhttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Receptor_(biochemistry)http://en.wikipedia.org/wiki/Cell_adhesion_moleculehttp://en.wikipedia.org/wiki/Cell_adhesion_moleculehttp://en.wikipedia.org/wiki/Growth_factorshttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Neurotransmittershttp://en.wikipedia.org/wiki/Hormonehttp://en.wikipedia.org/wiki/Signaling_moleculehttp://en.wikipedia.org/wiki/Signaling_moleculehttp://en.wikipedia.org/wiki/Integral_membrane_protein


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The binding initiates a chemical change on

the intracellular side of the membrane. In this

way the receptors play a unique and important

role in cellular communications and signaltransduction.
http://en.wikipedia.org/wiki/Intracellularhttp://en.wikipedia.org/wiki/Intracellular


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Types

Receptors can be roughly divided into two

major classes: intracellular receptors

and extracellular receptors.
http://en.wikipedia.org/wiki/Intracellularhttp://en.wikipedia.org/wiki/Extracellularhttp://en.wikipedia.org/wiki/Extracellularhttp://en.wikipedia.org/wiki/Intracellular


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Extracellular receptors

Extracellular receptors are integral transmembrane proteins and

make up most receptors. They span the plasma membrane of the

cell, with one part of the receptor on the outside of the cell and

the other on the inside. Signal transduction occurs as a result of a

ligand binding to the outside; the molecule does not passthrough the membrane. This binding stimulates a series of events

inside the cell; different types of receptor stimulate different

responses and receptors typically respond to only the binding of

a specific ligand. Upon binding, the ligand induces a change inthe conformation of the inside part of the receptor.These result

in either the activation of an enzyme in the receptor or the

exposure of a binding site for other intracellular signaling

proteins within the cell, eventually propagating the signal

through the cytoplasm.
http://en.wikipedia.org/wiki/Transmembrane_proteinhttp://en.wikipedia.org/wiki/Plasma_membranehttp://en.wikipedia.org/wiki/Chemical_conformationhttp://en.wikipedia.org/wiki/Chemical_conformationhttp://en.wikipedia.org/wiki/Plasma_membranehttp://en.wikipedia.org/wiki/Transmembrane_proteinhttp://en.wikipedia.org/wiki/Transmembrane_proteinhttp://en.wikipedia.org/wiki/Transmembrane_proteinhttp://en.wikipedia.org/wiki/Transmembrane_protein


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These are transmembrane recptors of various

types

Having 3 domains


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The extracellular domain

The extracellular domain is the part of the

receptor that sticks out of the membrane on the

outside of the cell or organelle. If the

polypeptide chain of the receptor crosses thebilayer several times, the external domain can

comprise several "loops" sticking out of the

membrane.
http://en.wikipedia.org/wiki/Organellehttp://en.wikipedia.org/wiki/Organelle


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the transmembrane domains

In the majority of receptors for which structural

evidence exists, transmembrane alpha

helices make up most of the transmembrane

domain. In certain receptors, such asthe nicotinic acetylcholine receptor, the

transmembrane domain forms a protein-lined

pore through the membrane, or ion channel.Upon activation of an extracellular domain by

binding of the appropriate ligand, the pore

becomes accessible to ions, which then pass
http://en.wikipedia.org/wiki/Transmembrane_helixhttp://en.wikipedia.org/wiki/Transmembrane_helixhttp://en.wikipedia.org/wiki/Acetylcholine_receptorhttp://en.wikipedia.org/wiki/Ion_channelhttp://en.wikipedia.org/wiki/Ion_channelhttp://en.wikipedia.org/wiki/Acetylcholine_receptorhttp://en.wikipedia.org/wiki/Transmembrane_helixhttp://en.wikipedia.org/wiki/Transmembrane_helixhttp://en.wikipedia.org/wiki/Transmembrane_helixhttp://en.wikipedia.org/wiki/Transmembrane_helix


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In other receptors, the transmembrane domains

are presumed to undergo a conformational

change upon binding, which exerts an effect

intracellularly. In some receptors, such asmembers of the 7TM superfamily, the

transmembrane domain may contain the ligand

binding pocket
http://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/Cytoplasm


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intracellular (or cytoplasmic)

domain The intracellular (or cytoplasmic) domain of the

receptor interacts with the interior of the cell or

organelle, relaying the signal. There are two

fundamentally different ways for this interaction: The intracellular domain communicates via specific

protein-protein-interactions with effector proteins, which

in turn send the signal along a signal chain to its

destination.

With enzyme-linked receptors, the intracellular domain

has enzymatic activity. Often, this is a tyrosine

kinase activity. The enzymatic activity can also belocated on an enz me associated with the intracellular
http://en.wikipedia.org/wiki/Cytoplasmhttp://en.wikipedia.org/wiki/Cytoplasmhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Cytoplasmhttp://en.wikipedia.org/wiki/Cytoplasm


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processes through membrane receptors involve

the External Reactions, in which the ligand

binds to a membrane receptor, and the Internal

Reactions, in which intracellular response istriggered.


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Based on structural and functional similarities,

membrane receptors are mainly divided into 3

classes: The ion channel-linked receptor;

The enzyme-linked receptor and G protein-coupled receptor.
http://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channel


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Ion channel linked receptors

Ion channel linked receptors are ion-channels

(including cation-channels and anion-channels)

themselves and constitute a large family of

multipass transmembrane proteins. They areinvolved in rapid signaling events most generally

found in electrically excitable cells such

as neurons and are also called ligand-gated ionchannels. Opening and closing of Ion channels

are controlled byneurotransmitters.
http://en.wikipedia.org/wiki/Ion_channel_linked_receptorshttp://en.wikipedia.org/wiki/Ion_channel_linked_receptorshttp://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Neurotransmittershttp://en.wikipedia.org/wiki/Neurotransmittershttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Ion_channel_linked_receptorshttp://en.wikipedia.org/wiki/Ion_channel_linked_receptors


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Enzyme-linked receptors

Enzyme-linked receptors are either enzymes

themselves, or are directly associated with the

enzymes that they activate. These are usually

single-pass transmembrane receptors, with theenzymatic portion of the receptor being

intracellular. The majority of enzyme-lined

receptors are protein kinases, or associate withprotein kinases.
http://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptorhttp://en.wikipedia.org/wiki/Enzyme-linked_receptor


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G protein-coupled receptors

G protein-coupled receptors are integral membrane

proteins that possess seven membrane-spanning

domains or transmembrane helices. These receptors

activate a G protein ligand binding. G-protein is atrimeric protein. The 3 subunits are called and .

The subunit can bind with guanosine diphosphate,

GDP. This causesphosphorylation of the GDP

to guanosine triphosphate, GTP, and activates the subunit, which then dissociates from the and

subunits. The activated subunit can further affect

intracellular signaling proteins or target functional

proteins directly.

r
http://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_proteinhttp://en.wikipedia.org/wiki/Guanosine_diphosphatehttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Guanosine_triphosphatehttp://en.wikipedia.org/wiki/Guanosine_triphosphatehttp://en.wikipedia.org/wiki/Guanosine_triphosphatehttp://en.wikipedia.org/wiki/Guanosine_triphosphatehttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Guanosine_diphosphatehttp://en.wikipedia.org/wiki/Guanosine_diphosphatehttp://en.wikipedia.org/wiki/Guanosine_diphosphatehttp://en.wikipedia.org/wiki/G_proteinhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptorhttp://en.wikipedia.org/wiki/G_protein-coupled_receptor


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GP

rotei

n-LinkedRec

eptor


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Signal transduction through membrane

receptors usually requires four characters:

Extracellular signal molecule: an extracellular

signal molecule is produced by one cell and is

capable of traveling to neighboring cells, or to

cells that may be far away.

Receptor protein: the cells in an organism musthave cell surface receptor proteins that bind to

the signal molecule and communicate its

presence inward into the cell.

four Stages of Signal Transductio


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Intracellular signaling proteins: these distribute

the signal to the appropriate parts of the cell.

The binding of the signal molecule to the

receptor protein will activate intracellularsignaling proteins that initiate a signaling cascade

(a series of intracellular signaling molecules that

act sequentially). Target proteins: the conformations or other

properties of the target proteins are altered

when a signaling pathway is active and changes


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hree Stages of Signal Transductio


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NEXT

Detailed role of G-protein in signal transduction


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