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  2. Adenosine 1. coupling of cellular metabolism to energy supply. 2. Suppresses neuronal firing and increases blood flow. 3. four types : A1, A2A, A2B, A3

  3. Adenosine in the brain 1. physiological neuromodulator 2. extracellular adenosine rises from nmol to mol under seizures, ischaemia and hypoxia 3. Function: a. neuroprotective effect mainly by A1 receptors.

  4. b. in neurons: inhibits the release of excitatory neurotransmitters  hyperpolarization. c. stimulation of glial adenosine receptors  synthesis of various neuroprotective substances. d. adenosine A1 receptor stimulation in astrocytes  release of nerve growth factor and S100B protein. e. stimulation of adenosine A2B receptors in astrocytes induces synthesis and release of interleukin-6 (IL-6).

  5. Selective adenosine receptor agonists: a. CPA (A1) and CGS 21680 (A2A) b. NECA: agonist, A3 receptors c. 8PT: antagonist, high affinity for A1, A2A, intermediate affinity for A2B, very low affinity for A3 adenosine receptors

  6. Adenosine production a. S-adenosylhomocysteine (SAH) by SAH hydrolaseto l-homocysteine and adenosine b. hydrolysisof AMP by 5'- nucleotidase, predominates during ischemic or hypoxicconditions.

  7. Potential signaling pathways for adenosine in modulating cardiomyocyte hypertrophy. a. Stimulator of Gq-coupled receptors a) norepinephrine phenylephrine angiotensin II endothelin-1 b) pathways: activates a Gq-PLC/PLD (phospholipase C , D) signaling pathway b. stimulator of Gs-coupled receptors a) ß1-adrenergic receptors (isoproterenol) b) pathway: activates the Gs-cAMP signaling pathway.

  8. c. Activation of Gq and Gs results: activation of Ca2+ and cAMP signaling → contractility and energy demands and results in hypertrophy d. Activation of the Gi-coupled adenosine A1receptor results: → inhibits Gs and Gq signaling and protects the myocytes from hypertrophy

  9. AdenosineA1receptor a. overexpression → increased myocardial resistance toischemia b. Adenosine inhibits norepinephrine release frompresynaptic vesicles→ attenuates the renin- angiotensin system,decreases endothelin-1 release, and exerts antiinflammatoryeffects

  10. Adenosine A1 and A3:contribute to myocardial preconditioningAdenosine A2Areceptors: a. vascularsystem → vasodilation. b. also foundin cardiac myocytes → coupling to cAMP (reported in rat but not in porcine) c. suggests: many adenosine effectshave the potential to influence the cardiac response to stress

  11. Adenosine: attenuate myocardial hypertrophy a. CAD (2-chloroadenosine ): a stable analogue of adenosine→ inhibitedthe hypertrophic response to phenylephrine, endothelin-1, angiotensinII, or isoproterenol. b. adenosine A1 agonist mimick (N-cyclopentyl adenosine , CPA) c. A2 or A3 agonists: did not

  12. FINE2006-12-7

  13. CN

  14. Molecular genetic analysis of the calcineurin signaling pathways

  15. 1. calcineurin :Ca2 and calmodulin-dependent protein phosphatase (type 2B)2. serine:threonine-specific protein phosphatases 3. target of the immunosuppressant drugreceptor4. Inhibitor: cyclosporin A (CsA)-cyclophilin and tacrolimus (FK506)-FKBP 5. Structure: heterodimer a. catalytic (calcineurin A) b. regulatory (calcineurin B) (fig. 1)

  16. Fig. 1

  17. 1. Molecular cloning studies identified 3 distinct genes encoding the , , isoforms of calcineurin A2.  and  isoforms serve different roles in neuronal signaling 3.  isoform is expressed in the testis4. calcineurin-mediated dephosphorylation and nuclear translocation is a central event in signal transduction, which responses to Ca2-mobilizing stimuli.

  18. T cell activation1. Inhibitors: CsA and FK506 for treat graft rejection 2. Pathway: T cell receptor (TCR)-activated signal transduction pathway3. Procedure: Antigen + TCR → Ca2↑→ calmodulin + calcineurin B → bind to Ca2 → moveaway Cn A from the catalytic active site of calcineurin → Cn activated

  19. 4. Cn→ dephosphorylates NF-AT (nuclear factor of activated T cells) → DNA recognition → bind with activator protein-1 (AP-1, transcription factor ) (fig. 2) Activated calcineurin5. Cn → dephosphorylates NF-AT → into nucleus → transcription of the T cell gene↑→ IL-2↑

  20. FIG.2

  21. INHIBITOR: immunosuppressants 1. CsA → bound to cyclophilin (receptor)2. FK506 → bound to FKBP3. The complexes → inhibit calcineurin →dephosphorylation↓→ activation of NF- AT↓→ suppression of the TCR-activated signal transduction pathway by CsA and FK506

  22. FIG. 3

  23. NF-AT kinases (fig. 1) counteracts calcineurin 1. c-Jun amino-terminal kinase (JNK): a. function: phosphorylate NF-AT4 b. JNK activation → nuclear exclusion of NF-AT42. Casein kinase Ia (CKIa): binds and phosphorylates NF-AT4→ inhibition of NF-AT4 nuclear translocation.

  24. 3. Mitogen-activatedprotein kinase:extracellular signal-regulated kinase kinase 1 (MEKK1) →stabilizing the interaction between NF- AT4 and CKI→ suppresses NF-AT4 nuclear import4. Glycogen synthase kinase-3 (GSK-3) : phosphorylation and translocation of NFAT

  25. Muscle hypertrophy1. cardiac hypertrophy: calcineurin→ NF-AT3 interacts with the cardiac zinc finger transcription factor GATA-4 → synergistic activation of cardiac transcription (fig. 2)2. Immunosuppressants prevented hypertrophic cardiomyopathy3. CsA: similar effect , suggesting similar pathway of T cell activation

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