Biologie Celulara si Histologie

Curs 6 Sisteme de semnalizare celulara

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

Cuprins
Definitie
Clasificari
Notiuni de baza:
Semnale
Receptori, liganzi

Mesageri primi, mesageri secunzi

Cai de semnalizare de baza

Cai de semnalizare complexe

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Biologie Celulara si Histologie 6. Semnalizare celulara

Definitie
Semnalizarea celulara = transmiterea

informatiei in interiorul unei celule si intre celule

diferite

Comunicarea intercelulara se afla la baza

functionarii organismelor

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Biologie Celulara si Histologie 6. Semnalizare celulara

Clasificari
Semnalizare endocrina

Semnalele ajung la celula prin

sange, dupa ce au fost produse si
secretate intr-o glanda cu secretie
interna

Semnalizare paracrina

Semnalele produse de o celula

influenteaza activitatea celulelor din
jur

Semnalizare autocrina

O celula isi automoduleaza

activitatea prin secretia de factori
umorali

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Biologie Celulara si Histologie 6. Semnalizare celulara

Notiuni de baza
Receptor

Proteina situata in membrana / citoplasma / nucleu

Legarea unei molecule (= ligand) determina modificarea conformationala

a acestuia cascada de alte modificari ale unor componente celulare,
cu rezultat final un raspuns celular

Ligand

Molecula care se leaga cu un grad mai mic sau mai mare de specificitate
de un anumit receptor

Liganzii pot fi:

Agonisti determina activarea receptorului

Antagonisti - determina inactivarea / blocarea receptorului

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Biologie Celulara si Histologie 6. Semnalizare celulara

Legarea liganzilor la receptori

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Biologie Celulara si Histologie 6. Semnalizare celulara

Notiuni de baza
Mesager prim

Ligandul care, prin legarea de receptor, declanseaza o

cascada de modificari care are ca efect final un raspuns
celular

Mesageri secund

Molecule sintetizate in urma activarii receptorului de

catre mesagerul prim

Activeaza un sistem enzimatic cu rol in raspunsul

celular

Au rol de amplificare a semnalelor

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Biologie Celulara si Histologie 6. Semnalizare celulara

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

Receptori celulari
Receptori membranari
Ionotropici (canale ionice)
Metabotropici

Cuplati cu proteine G
Cuplati cu enzime (kinaze)

Receptori intracelulari
Citoplasmatici (de obicei, pentru mesageri secunzi)
Nucleari

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Biologie Celulara si Histologie 6. Semnalizare celulara

Receptori ionotropici

Receptori nicotinici ptr ACh

Receptori pentru GABA (GABAA,C)
Receptori pentru glicina
Receptori pentru serotonina
Receptori pentru glutamat (AMPA, NMDA, rec. ptr kainat)
Receptori pentru ATP (P2X)

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Biologie Celulara si Histologie 6. Semnalizare celulara

Cai de semnalizare implicand receptori ionotropici

Contractia musculara

http://www.blackwellpublishing.com/matthews/myosin2.swf

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Biologie Celulara si Histologie 6. Semnalizare celulara

Receptori cuplati cu proteine G (GPCR)

Foarte multe tipuri

Implicati in:

Perceptia vizuala, olfactiva

Neurotransmisia vegetativa si in sistemul nervos central (roluri modulatoare, frecvent)

Roluri modulatoare in lanturile de semnalizare ale sistemului imun

Exemple:

Receptori muscarinici pentru acetilcolina

Receptori muscarinici pentru GABA

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Biologie Celulara si Histologie 6. Semnalizare celulara

Diversity of G Protein-Coupled Receptor

Signal Transduction Pathways

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Biologie Celulara si Histologie 6. Semnalizare celulara

Diversity of G Protein-Coupled Receptor

Signal Transduction Pathways
Receptors coupled to heterotrimeric GTP-binding proteins (G proteins) are
integral transmembrane proteins that transduce extracellular signals to the cell
interior. G protein-coupled receptors exhibit a common structural motif
consisting of seven membrane spanning regions. Receptor occupation promotes
interaction between the receptor and the G protein on the interior surface of the
membrane. This induces an exchange of GDP for GTP on the G protein subunit
and dissociation of the subunit from the heterodimer. Depending on its
isoform, the GTP- subunit complex mediates intracellular signaling either
indirectly by acting on effector molecules such as adenylyl cyclase (AC) or
phospholipase C (PLC), or directly by regulating ion channel or kinase function.
References
Schoneberg, T., et al., Structural basis of G protein-coupled receptor function.
Mol. Cell. Endocrinol., 151, 181-193 (1999).
LeVine, H., 3rd., Structural features of heterotrimeric G protein-coupled receptors
and their modulatory proteins. Mol. Neurobiol., 19, 111-149 (1999).
Morris, A.J., et al., Physiological regulation of G protein-linked signaling. Physiol.
Rev., 79, 1373-1430 (1999).

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Biologie Celulara si Histologie 6. Semnalizare celulara

Cai de semnalizare implicand receptori cuplati cu proteine G

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

Calea de semnalizare a adrenalinei

http://bcs.whfreeman.com/thelifewire/content/chp15/1501.swf
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Biologie Celulara si Histologie 6. Semnalizare celulara

Receptori cuplati cu enzime (RTK)

Proteina receptor are activitate de tirozin-kinaza (protein-kinaza),

in forma fosforilata

Categoria cuprinde receptori pentru:

Factori de crestere

Hormoni

Citokine

Exemplu: receptorul pentru insulina

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Biologie Celulara si Histologie 6. Semnalizare celulara

Familia protein-kinazelor umane

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Biologie Celulara si Histologie 6. Semnalizare celulara

Receptori citoplasmatici
Sunt receptori activati de mesageri secunzi in lanturile de

semnalizare

Exemple:

Receptorul pentru IP3 din reticulul endoplasmic

Receptorul ryanodinic din fibra musculara striata sau miocardica

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Biologie Celulara si Histologie 6. Semnalizare celulara

Receptori nucleari
(factori de transcriptie)
Activarea lor influenteaza direct transcrierea

informatiei din ADN in ARN (receptorul activat

se leaga direct de ADN si influenteaza
transcrierea genelor adiacente)

Exemple:

Receptori hormonali:

Hormoni corticoizi
Hormoni tiroidieni

Estrogeni

Receptori pentru unii factori de crestere

Receptori pentru retinoizi

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Biologie Celulara si Histologie 6. Semnalizare celulara

Calea de semnalizare a corticoizilor

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Biologie Celulara si Histologie 6. Semnalizare celulara

Glucocorticoid Receptor Signaling

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Glucocorticoid Receptor Signaling

The glucocorticoid hormone, cortisol, passes through the plasma membrane into the
cytoplasm where it binds to the specific, high-affinity glucocorticoid receptor (GR). The
resulting complex is the non-DNA-binding oligomer of the GR, in which the receptor is
complexed with other proteins. In this complex, the DNA-binding domain of the receptor
is bound by the heat shock protein 90 (hsp90) dimer. Other proteins in this complex
include heat shock protein 70 (hsp70) and FKBP52. Dissociation of the oligomeric
complex yields the free cortisol-receptor subunit in the DNA-binding form. The activated
receptor forms a homodimer and is translocated to the nucleus through the nucleopore.
Inside the nucleus, the receptor complex binds to specific DNA responsive elements
(GRE) to activate gene transcription.
References
Bruner, K.L., et al., The unliganded mineralocorticoid receptor is associated with heat
shock proteins 70 and 90 and the immunophilin FKBP-52. Recept. Signal Transduct., 7,
85-98 (1997).
Drouin, J., et al., Homodimer formation is rate-limiting for high affinity DNA binding by
glucocorticoid receptor. Mol Endocrinol., 6, 1299-1309 (1992).

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Biologie Celulara si Histologie 6. Semnalizare celulara

Calea de semnalizare a tiroxinei

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Biologie Celulara si Histologie 6. Semnalizare celulara

Cai de semnalizare implicand receptori nucleari

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Biologie Celulara si Histologie 6. Semnalizare celulara

Mesageri secunzi

Tipuri:

Molecule hidrofobe: DAG (diacil glicerol), IP3 (inozitol trifosfat), PI

(fosfatidil inozitoli); sunt molecule asociate membranei, pot difuza
prin membrana pana in spatiul din apropiere, unde controleaza
activitatea proteinelor efectoare asociate membranei
Molecule hidrofile: cAMP, cGMP, Ca2+; situate in citoplasma,
actioneaza asupra unor efectori citoplasmatici
Gaze: NO (oxid nitric), CO (monoxidul de carbon); pot difuza atat
prin membrane, cat si prin citoplasma
DAG

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cAMP

Biologie Celulara si Histologie 6. Semnalizare celulara

Amplificarea semnalului prin mesageri

secunzi

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Biologie Celulara si Histologie 6. Semnalizare celulara

Cyclic Nucleotide Metabolism - cAMP

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Biologie Celulara si Histologie 6. Semnalizare celulara

Second Messenger Systems Involved in

Reward and Addiction

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Biologie Celulara si Histologie 6. Semnalizare celulara

Second Messenger Systems Involved in

Reward and Addiction
With repeated psychostimulant administration, these are changes in dopaminergic and
glutamatergic transmission in the nucleus accumbens. The figure depicts the major second
messenger systems in the nucleus accumbens activated by dopamine and glutamate that are
influenced by acute and/or repeated psychostimulant injections.

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Biologie Celulara si Histologie 6. Semnalizare celulara

Cyclic Nucleotide Metabolism - cAMP

Cyclic nucleotides have been extensively studied as second messengers of
intracellular events initiated by activation of many types of hormone and
neurotransmitter receptors. Receptors that stimulate the conversion of ATP to
cyclic 3, 5-adenosine monophosphate (cAMP) are associated with G proteins.
Binding of the hormone or neurotransmitter to its membrane-bound receptor
induces a conformational change in the receptor that leads to activation of the
-subunit of the G protein. The activated Gs subunit stimulates, while the Gi
subunit inhibits adenylyl cyclase (AC). Stimulation of AC catalyzes the conversion
of cytoplasmic ATP to cAMP. cAMP activates cAMP-dependent protein kinases,
including protein kinase A (PKA). By catalyzing the phosphorylation (activation or
deactivation) of intracellular enzymes, cAMP-dependent kinases elicit a wide
array of metabolic and functional processes. Negative regulation can occur in the
pathway when phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP to
adenosine-5-monophosphate (5-AMP). Several families of phosphodiesterases
(PDE-I-VI) act as regulatory switches by catalyzing the degradation of cAMP to
adenosine-5-monophosphate (5-AMP). PDE II is a low affinity PDE that can
cleave both cAMP and cGMP. The activity of PDE II is stimulated by cGMP. PDE III
is a low affinity PDE that is inhibited by cGMP and is involved in the regulation of
smooth muscle and cardiac contraction. PDE IV is highly selective for cAMP and
is the high affinity PDE present in most cell types.
References
Francis, S.H., and Corbin, J.D., Cyclic nucleotide-dependent protein kinases:
intracellular receptors for cAMP and cGMP action. Crit. Rev. Clin. Lab. Sci., 36,
275-328 (1999).
Juilfs, D.M., et al., Cyclic GMP as substrate and regulator of cyclic nucleotide
phosphodiesterases (PDEs). Rev. Physiol. Biochem. Pharmacol., 135, 67-104
(1999).
Simonds, W.F., G protein regulation of adenylate cyclase. Trends Pharmacol. Sci.,
20, 66-73 (1999).

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Biologie Celulara si Histologie 6. Semnalizare celulara

Exemple de cai de semnalizare

complexe

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

Calea de semnalizare a proliferarii celulare

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Biologie Celulara si Histologie 6. Semnalizare celulara

Wikimedia Commons

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Biologie Celulara si Histologie 6. Semnalizare celulara

Wikimedia Commons

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

SIGMA-ALDRICH

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Biologie Celulara si Histologie 6. Semnalizare celulara

Insulin Pathway
Signaling through the insulin pathway is critical for the regulation of intracellular
and blood glucose levels and the avoidance of diabetes. Insulin binds to its
receptor leading to the autophosphorylation of the -subunits and the tyrosine
phosphorylation of insulin receptor substrates (IRS). IRS phosphorylates the SH2
domain of Shp2, a tyrosine phosphatase, and the SH3 domain of the adaptor
molecule Grb2. Activated Grb2 recruits Sos1 that, in turn, activates the Ras
signaling pathway and gene transcription. IRS also activates phosphoinositide 3kinase (PI3K) through its SH2 domain, thus increasing the intracellular
concentration of PIP2 and PIP. This, in turn, activates phosphatidylinositol
phosphate-dependent kinase-1 (PDK-1), that subsequently activates Akt/PKB This
results in the translocation of the glucose transporter (GLUT4) from cytoplasmic
vesicles to the cell membrane.
References
Bevan, P., Insulin signaling. J. Cell Sci., 114, 1429-1430 (2001).
Kido, Y., et al., Clinical review 125: The insulin receptor and its cellular targets. J.
Clin. Endocrinol. Metab., 86, 972-979 (2001).

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Biologie Celulara si Histologie 6. Semnalizare celulara

Diabetes 52(12):2867-2873,
2003

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Shi et al. Molecular Pain 2005

1:33

Biologie Celulara si Histologie 6. Semnalizare celulara

Disulfide relays and phosphorylative

cascades: partners in redox-mediated
signaling pathways
G Filomeni, G Rotilio and M R Ciriolo

Cell Death and Differentiation (2005) 12, 15551563.

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara

Bibliografie suplimentara

http://pid.nci.nih.gov/browse_pathways.shtml#NCI-Nature

http://highered.mcgraw-hill.com/sites/dl/free/0072437316/120060/ravenanimation.html

http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.html

http://www.hhmi.org/biointeractive/neuroscience/lectures.html

DBB Masterat Inginerie Medicala si Clinica

Biologie Celulara si Histologie 6. Semnalizare celulara