A1 Trasduzione Del Segnale 02 10 2014.Ppt

8/18/2019 A1 Trasduzione Del Segnale 02 10 2014.Ppt

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Cells are alert detectors, sensing and interpreting information constantly to adjustto the environment and coordinate activities with surrounding cells

Signals can inform about

•

T, light, pH, Ionic force, pressure• availability of O2, nutrients, proliferative and anti-proliferative factors• presence of competitors, mating partners, predators or preys, infectious agents•

genome status

A cell can respond to signals by•

changing the genes that it transcribes•

altering the cell surface• modifying proteins and enzyme activities• moving materials between compartments•

remodelling its cytoskeleton• migrating• dying

Cell-to-cell communication is essential for multicellular organisms

• Cell junction

• Cell-cell recognition

•

Cell signalling



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Gap junctions

between animal cells

Cell junctions

Cell-cell recognition

Plasmodesmata

between plant cells

Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacentcells

In local signaling, animal cells may communicate by direct contact

(a)

Cell junctions and contact-dependent signaling



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• Local- paracrine, synaptic signaling

• Long-distance- hormonal signaling (endocrine)• Autocrine

Paracrine signaling

Local regulatordiffuses through

extracellular fluid

Secretoryvesicle

Secretingcell

Target cell

Local signaling

Electrical signalalong nerve celltriggers release of

neurotransmitter

Neurotransmitterdiffuses across

synapse

Endocrine cell Bloodvessel

Long-distance signaling

Hormone travelsin bloodstreamto target cells

Synaptic signaling

Target cell

is stimulated

Hormonal signaling

Targetcell

Cell to cell communication by Signaling



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The Three Stages of Cell Signaling

• Reception

• Transduction

• Response



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EXTRACELLULARFLUID

Reception

Plasma membrane

Transduction

CYTOPLASM

Receptor

Signalmolecule

Relay molecules in a signal transductionpathway

Transduction• Usually involves multiple steps

alteration of the activity, by conformational changes, or localization of

intracellular signal proteins (enzymes and adaptors proteins)production of second messengers

• Multistep pathways can amplify a signal

Signal transduction pathways: the diverse sequences of events between receptoractivation and cellular responses.



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EXTRACELLULARFLUID

Reception

Plasma membrane

Transduction

CYTOPLASM

Receptor

Signalmolecule

Relay molecules in a signal transduction

pathway

Response

Activationof cellularresponse

ResponseSignal transduction pathways lead to regulation of one or more cellular activities

• change the permeability, transport properties, or electrical state of cell• cell metabolism• cell secretory activity

• cell rate of proliferation and differentiation• cell contractile activity• cell migration• cell death



Figure 15-6 Molecular Biology of the Cell (© Garland Science 2008)

Two major types of responses exist:1) changes in the activity or function of specific pre-existing proteins2) changes in the amounts of specific proteins, as result of alteration of gene expression

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Each cell can responde to specific combination of extracellular signal molecules




Some signal molecules induce different responsesin different cells of a same organism



The specific response of a single cell or tissueto a specific external stimulus depend by

• specific receptors-pattern endowed

•

specific intracellular trasducing machinery endowed

A same response in a cell can be induced bydifferent signal molecules, or different ligand/receptorcomplexes, if a common intracellular signaling circuit is

activated

i.e. epinefrin, glucagon and ACTH promote glicogen demolition in the liver cellsby interacting with different receptors that lead all to an increase in theintracellular level of a signal molecule, cAMP.

Signal trasduction mechanisms are well conserved



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La velocità con cui una cellula risponde alla rimozione del segnale dipende da

velocità di distruzione o turnover delle molecole influenzate dal segnale.E tale velocità di turnover determina anche la prontezza della risposta quandoarriva un nuovo segnale.



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Reception

• Intracellular receptors

• Receptors in the plasma membrane



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• Some receptor proteinsare intracellular, found inthe cytosol or nucleus oftarget cells

• Small or hydrophobicchemical messengers(steroids, retinoids, thyroid

hormones, vitamin D) canreadily cross themembrane and activatereceptors

• An activated hormone-receptor complex can actas a transcription factor,turning on specific genes

EXTRACELLULARFLUID

Plasmamembrane

The steroidhormone testosteronepasses through the

plasma membrane.

Testosterone bindsto a receptor proteinin the cytoplasm,

activating it.

The hormone-

receptor complexenters the nucleus

and binds to specificgenes.

The bound proteinstimulates thetranscription of

the gene into mRNA.

The mRNA istranslated into aspecific protein.

CYTOPLASM

NUCLEUS

DNA

Hormone(testosterone)

Receptorprotein

Hormone-receptorcomplex

mRNA

New protein

Intracellular Receptors



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EXCURSUS

Transcription factors

are regulatory proteins that influence gene transcription.

help RNA polymerase bind to the promoter region on DNA.



Figure 15-15a Molecular Biology of the Cell (© Garland Science 2008)



Figure 15-15b Molecular Biology of the Cell (© Garland Science 2008)



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Receptors in the Plasma Membrane• Most water-soluble signal molecules (eg. epinephrine, insulin, growth hormones)

bind to specific sites on receptor proteins in the plasma membrane

•

There are three main types of membrane receptors:

Ion channel-linkedreceptors

G-protein-linkedreceptors

Enzyme-linkedreceptors




Hypothetical intracellulars i g n a l i n g p a t h w a yactivated by a plasma-membrane receptor

The nomenclature of s ignalingpathways is quite arbitrary!

Extracellular signals (1° messengers)ReceptorsIntracellular transducing protein/enzyme

Intracellular small molecules (2° messengers)



Four features of Signal transducing systems




Molecular switches in signal transduction



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Binding of a signalling molecule (ligand) to the receptor

Growth hormone(ligand)

Growth hormonereceptor

Binding depends onweak, non covalent forces

(i.e. ionic, van der Waals, hydrophobic interactions)and

molecular complementaritybetween the interacting surface of a receptor and ligand

Receptor dimerizationLigand/Receptor complex

Identified by mutational studies



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The maximal physiological response to manyexternal signals occurs when only a fraction ofthe receptor molecules are occupied by ligand.

Binding of a signalling molecule (ligand) to the receptor

Kd=koff /Kon



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Synthetic analogs of natural hormonescan be divided in:

AgonistsMimic the function of a natural hormoneby binding its receptor and inducing response

AntagonistsBind to the receptor but induce no response

Examples

IP binds EP receptors tenfold more strongly

(used in treating bronchial asthma, etc..)

EP promotes relaxation of bronchial smooth muscle

EP increases contraction rate of bronchial smooth muscle

Beta-blocker

AP binds EP receptors with high affinity(used in treating cardiac arhythmias etc..)

contrazione

decontrazione To note:different effect of EPon different type of

cells target



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Receptors



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Clustering of membrane proteinsmediated by cytosolic adapter proteinscontaining multiple protein bindingdomains, as PDZ-domain.

Receptors

rarely are uniformly distributed on the cell surface of cell target(es. Epinephrine receptors in adipose cells)

commonly are clusterized with other signalling proteins in a particular region of the cellsurface(es. Neurotrasmitters receptors in postsynaptic cell)

PDZ-domains bindto the sequence Ser/Thr-X- or -X-



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Lipids Rafts(Caveolae in mammalian cells)

Signal proteins may be recruitedto such membrane domains- by scaffold proteins- by insertion of lipid anchors- by pleckstrin homology or other lipid-binding domains

Microdomains or Aggregates of certain lipids (cholesterol and sphingolipids) in theplasma membranecontaining several different receptors and other signaling proteins

marked by the presence of caveolina

A1 Trasduzione Del Segnale 02 10 2014.Ppt

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