adenosine receptor 2006-12-7
DESCRIPTION
ADENOSINE RECEPTOR 2006-12-7. Adenosine 1. coupling of cellular metabolism to energy supply. 2. Suppresses neuronal firing and increases blood flow. 3. four types : A1, A2A, A2B, A3. - PowerPoint PPT PresentationTRANSCRIPT
ADENOSINE RECEPTOR
2006-12-7
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 m
ol 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 synt
hesis 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
hydrolase to l-homocysteine and adenosine
b. hydrolysis of AMP by 5'- nucleotidase, pre
dominates during ischemic or hypoxic con
ditions.
Potential signaling pathways for adenosine in modulating car
diomyocyte 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 A1 receptor res
ults: → inhibits Gs and Gq signaling and protects the
myocytes from hypertrophy
Adenosine A1 receptor
a. overexpression → increased myocardial resistance to
ischemia
b. Adenosine inhibits norepinephrine release from
presynaptic vesicles→ attenuates the renin-
angiotensin system, decreases endothelin-1
release, and exerts antiinflammatory effects
Adenosine A1 and A3:
contribute to myocardial preconditioning
Adenosine A2A receptors:
a. vascular system → vasodilation.
b. also found in cardiac myocytes → coupling to
cAMP ( reported in rat but not in porcine)
c. suggests: many adenosine effects have the
potential to influence the cardiac response to
stress
Adenosine: attenuate myocardial hypertrophy
a. CAD (2-chloroadenosine ): a stable analogue of ade
nosine→ inhibited the hypertrophic response to phenylephr
ine, endothelin-1, angiotensin II, or isoproterenol.
b. adenosine A1 agonist mimick (N-cyclopentyl ade
nosine , CPA)
c. A2 or A3 agonists: did not
FINE
2006-12-7
CN
Molecular genetic analysis of the calcineurin signaling pathways
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)
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 fa
ctor of activated T cells) → DNA recogn
ition → bind with activator protein-1 (A
P-1, transcription factor ) (fig. 2) Activated ca
lcineurin
5. Cn → dephosphorylates NF-AT → into nu
cleus → transcription of the T cell gene↑
→ IL-2↑
FIG.2
INHIBITOR: immunosuppressants
1. CsA → bound to cyclophilin (receptor)
2. FK506 → bound to FKBP
3. The complexes → inhibit calcineurin →d
ephosphorylation↓ → activation of NF- AT
↓ → suppression of the TCR-activated sig
nal transduction pathway by CsA and FK506
FIG. 3
NF-AT kinases (fig. 1) counteracts calcineurin 1. c-Jun amino-terminal kinase (JNK):
a. function: phosphorylate NF-AT4b. JNK activation → nuclear exclusion of
NF-AT42. Casein kinase Ia (CKIa): binds and phosphorylates NF-AT4→ inhibition of
NF-AT4 nuclear translocation.
3. Mitogen-activated protein kinase:extracellu
lar signal-regulated kinase kinase 1 (MEKK1)
→stabilizing the interaction between NF-
AT4 and CKI → suppresses NF-AT4 nu
clear import
4. Glycogen synthase kinase-3 (GSK-3) : ph
osphorylation 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
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