Adenosine 1. coupling of cellular metabolism to energy supply. 2. Suppresses neuronal firing and increases blood flow. 3. four types : A1, A2A, A2B, A3
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.
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).
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
Adenosine production a. S-adenosylhomocysteine (SAH) by SAH hydrolaseto l-homocysteine and adenosine b. hydrolysisof AMP by 5'- nucleotidase, predominates during ischemic or hypoxicconditions.
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.
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
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
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
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
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)
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.
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
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↑
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
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.
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
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