DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Biologie Celulara si HistologieBiologie Celulara si Histologie

Curs 6 – Sisteme de semnalizare celularaCurs 6 – Sisteme de semnalizare celulara

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

CuprinsCuprins

⇨DefinitieDefinitie

⇨ClasificariClasificari

⇨Notiuni de baza:Notiuni de baza:► SemnaleSemnale

► Receptori, liganziReceptori, liganzi

► Mesageri primi, mesageri secunziMesageri primi, mesageri secunzi

⇨Cai de semnalizare de bazaCai de semnalizare de baza

⇨Cai de semnalizare complexeCai de semnalizare complexe

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

DefinitieDefinitie

⇨Semnalizarea celulara Semnalizarea celulara = transmiterea = transmiterea informatiei in interiorul unei celule si intre celule informatiei in interiorul unei celule si intre celule diferitediferite

⇨Comunicarea intercelulara se afla la baza Comunicarea intercelulara se afla la baza functionarii organismelorfunctionarii organismelor

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

ClasificariClasificari

⇨Semnalizare endocrinaSemnalizare endocrina Semnalele ajung la celula prin Semnalele ajung la celula prin

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

⇨Semnalizare paracrinaSemnalizare paracrina Semnalele produse de o celula Semnalele produse de o celula

influenteaza activitatea celulelor din influenteaza activitatea celulelor din jurjur

⇨Semnalizare autocrinaSemnalizare autocrina O celula isi automoduleaza O celula isi automoduleaza

activitatea prin secretia de factori activitatea prin secretia de factori umoraliumorali

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Notiuni de bazaNotiuni de baza

⇨ReceptorReceptor Proteina situata in membrana / citoplasma / nucleuProteina situata in membrana / citoplasma / nucleu

Legarea unei molecule (= ligand) determina modificarea conformationala Legarea unei molecule (= ligand) determina modificarea conformationala a acestuia → cascada de alte modificari ale unor componente celulare, a acestuia → cascada de alte modificari ale unor componente celulare, cu rezultat final un raspuns celularcu rezultat final un raspuns celular

⇨Ligand Ligand Molecula care se leaga cu un grad mai mic sau mai mare de specificitate Molecula care se leaga cu un grad mai mic sau mai mare de specificitate

de un anumit receptorde un anumit receptor

Liganzii pot fi:Liganzii pot fi:

► AgonistiAgonisti – determina activarea receptorului– determina activarea receptorului

► AntagonistiAntagonisti - determina inactivarea / blocarea receptorului - determina inactivarea / blocarea receptorului

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Legarea liganzilor la receptoriLegarea liganzilor la receptori

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Notiuni de bazaNotiuni de baza

⇨Mesager primMesager prim Ligandul care, prin legarea de receptor, declanseaza o Ligandul care, prin legarea de receptor, declanseaza o

cascada de modificari care are ca efect final un raspuns cascada de modificari care are ca efect final un raspuns celularcelular

⇨Mesageri secundMesageri secund Molecule sintetizate in urma activarii receptorului de Molecule sintetizate in urma activarii receptorului de

catre mesagerul primcatre mesagerul prim

Activeaza un sistem enzimatic cu rol in raspunsul Activeaza un sistem enzimatic cu rol in raspunsul celularcelular

Au rol de amplificare a semnalelor Au rol de amplificare a semnalelor

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

Receptori celulariReceptori celulari

⇨Receptori membranariReceptori membranari► Ionotropici (canale ionice)Ionotropici (canale ionice)

► MetabotropiciMetabotropici◗ Cuplati cu proteine GCuplati cu proteine G◗ Cuplati cu enzime (kinaze)Cuplati cu enzime (kinaze)

⇨Receptori intracelulariReceptori intracelulari► Citoplasmatici (de obicei, pentru mesageri secunzi)Citoplasmatici (de obicei, pentru mesageri secunzi)

► NucleariNucleari

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Receptori ionotropiciReceptori ionotropici

⇨ Receptori nicotinici ptr AChReceptori nicotinici ptr ACh

⇨ Receptori pentru GABA (GABAReceptori pentru GABA (GABAA,CA,C))

⇨ Receptori pentru glicinaReceptori pentru glicina

⇨ Receptori pentru serotoninaReceptori pentru serotonina

⇨ Receptori pentru glutamat (AMPA, NMDA, rec. ptr kainat)Receptori pentru glutamat (AMPA, NMDA, rec. ptr kainat)

⇨ Receptori pentru ATP (P2X)Receptori pentru ATP (P2X)

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Cai de semnalizare implicand receptori ionotropiciCai de semnalizare implicand receptori ionotropici

Contractia muscularaContractia musculara

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

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Receptori cuplati cu proteine G (GPCR)Receptori cuplati cu proteine G (GPCR)

⇨ Foarte multe tipuriFoarte multe tipuri

⇨ Implicati in:Implicati in:➔ Perceptia vizuala, olfactivaPerceptia vizuala, olfactiva

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

➔ Roluri modulatoare in lanturile de semnalizare ale sistemului imunRoluri modulatoare in lanturile de semnalizare ale sistemului imun

⇨ Exemple:Exemple:

► Receptori muscarinici pentru acetilcolinaReceptori muscarinici pentru acetilcolina

► Receptori muscarinici pentru GABAReceptori muscarinici pentru GABA

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Diversity of G Protein-Coupled Receptor Signal Transduction Pathways

SIGMA-ALDRICH

Diversity of G Protein-Coupled Receptor Signal Transduction Pathways

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Diversity of G Protein-Coupled Receptor Signal Transduction PathwaysReceptors 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 α subunit and dissociation of the α subunit from the βγ heterodimer. Depending on its isoform, the GTP-α 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.ReferencesSchoneberg, 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).

Diversity of G Protein-Coupled Receptor Signal Transduction PathwaysReceptors 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 α subunit and dissociation of the α subunit from the βγ heterodimer. Depending on its isoform, the GTP-α 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.ReferencesSchoneberg, 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).

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Cai de semnalizare implicand receptori cuplati cu proteine GCai de semnalizare implicand receptori cuplati cu proteine G

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

http://bcs.whfreeman.com/thelifewire/content/chp15/1501.swf

Calea de semnalizare a adrenalineiCalea de semnalizare a adrenalinei

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Receptori cuplati cu enzime (RTK)Receptori cuplati cu enzime (RTK)

⇨ Proteina receptor are activitate de tirozin-kinaza (protein-kinaza), Proteina receptor are activitate de tirozin-kinaza (protein-kinaza), in forma fosforilatain forma fosforilata

⇨ Categoria cuprinde receptori pentru:Categoria cuprinde receptori pentru:

➔ Factori de crestereFactori de crestere➔ HormoniHormoni➔ CitokineCitokine

⇨ Exemplu: receptorul pentru insulinaExemplu: receptorul pentru insulina

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Familia protein-kinazelor umaneFamilia protein-kinazelor umane

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Receptori citoplasmaticiReceptori citoplasmatici

⇨ Sunt receptori activati de mesageri secunzi in lanturile de Sunt receptori activati de mesageri secunzi in lanturile de semnalizaresemnalizare

⇨ Exemple: Exemple:

► Receptorul pentru IP3 din reticulul endoplasmicReceptorul pentru IP3 din reticulul endoplasmic

► Receptorul ryanodinic din fibra musculara striata sau miocardicaReceptorul ryanodinic din fibra musculara striata sau miocardica

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

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

informatiei din ADN in ARN (receptorul activat informatiei din ADN in ARN (receptorul activat se leaga direct de ADN si influenteaza se leaga direct de ADN si influenteaza transcrierea genelor adiacente)transcrierea genelor adiacente)

⇨ Exemple:Exemple:

► Receptori hormonali:Receptori hormonali:◗ Hormoni corticoiziHormoni corticoizi

◗ Hormoni tiroidieniHormoni tiroidieni

◗ EstrogeniEstrogeni

► Receptori pentru unii factori de crestereReceptori pentru unii factori de crestere

► Receptori pentru retinoiziReceptori pentru retinoizi

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Calea de semnalizare a corticoizilorCalea de semnalizare a corticoizilor

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Glucocorticoid Receptor Signaling SIGMA-ALDRICH

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Glucocorticoid Receptor SignalingThe 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.ReferencesBruner, 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).

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Calea de semnalizare a tiroxineiCalea de semnalizare a tiroxinei

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Cai de semnalizare implicand receptori nucleariCai de semnalizare implicand receptori nucleari

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Mesageri secunziMesageri secunzi

⇨ Tipuri:Tipuri:

➔ Molecule hidrofobe:Molecule hidrofobe: DAG (diacil glicerol), IP3 (inozitol trifosfat), PI DAG (diacil glicerol), IP3 (inozitol trifosfat), PI (fosfatidil inozitoli); sunt molecule asociate membranei, pot difuza (fosfatidil inozitoli); sunt molecule asociate membranei, pot difuza prin membrana pana in spatiul din apropiere, unde controleaza prin membrana pana in spatiul din apropiere, unde controleaza activitatea proteinelor efectoare asociate membraneiactivitatea proteinelor efectoare asociate membranei

➔ Molecule hidrofile:Molecule hidrofile: cAMP, cGMP, Ca cAMP, cGMP, Ca2+2+; situate in citoplasma, ; situate in citoplasma, actioneaza asupra unor efectori citoplasmaticiactioneaza asupra unor efectori citoplasmatici

➔ Gaze:Gaze: NO (oxid nitric), CO (monoxidul de carbon); pot difuza atat NO (oxid nitric), CO (monoxidul de carbon); pot difuza atat prin membrane, cat si prin citoplasmaprin membrane, cat si prin citoplasma

DAG cAMP

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Amplificarea semnalului prin mesageri Amplificarea semnalului prin mesageri secunzisecunzi

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Cyclic Nucleotide Metabolism - cAMP

SIGMA-ALDRICHCyclic Nucleotide Metabolism - cAMP

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Second Messenger Systems Involved in Reward and Addiction SIGMA-ALDRICH

DBB – Masterat Inginerie Medicala si Clinica 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.

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Cyclic Nucleotide Metabolism - cAMPCyclic 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 α-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.ReferencesFrancis, 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).

Cyclic Nucleotide Metabolism - cAMPCyclic 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 α-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.ReferencesFrancis, 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).

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Exemple de cai de semnalizare Exemple de cai de semnalizare complexecomplexe

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Calea de semnalizare a proliferarii celulareCalea de semnalizare a proliferarii celulare

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Wikimedia Commons

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Wikimedia Commons

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Insulin Pathway

SIGMA-ALDRICH

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Insulin PathwaySignaling 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 ß-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 3-kinase (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.ReferencesBevan, 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).

DBB – Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie – 6. Semnalizare celulara

Shi et al. Molecular Pain 2005 1:33

Diabetes 52(12):2867-2873, 2003

DBB – Masterat Inginerie Medicala si Clinica 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, 1555–1563.

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 suplimentaraBibliografie suplimentara

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

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

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

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