Download Adenosine

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
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
hydrolase to l-homocysteine and adenosine
b. hydrolysis of AMP by 5'- nucleotidase,
predominates during ischemic or hypoxic
conditions.
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 A1 receptor
results: → 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
adenosine→ inhibited the hypertrophic response to
phenylephrine, endothelin-1, angiotensin II, or
isoproterenol.
b. adenosine A1 agonist mimick (N-cyclopentyl
adenosine , 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 drugreceptor
4. 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 A
2.  and  isoforms serve different roles in
neuronal signaling
3.  isoform is expressed in the testis
4. calcineurin-mediated dephosphorylation and
nuclear translocation is a central event in
signal transduction, which responses to
Ca2-mobilizing stimuli.
T cell activation
1. Inhibitors: CsA and FK506 for treat graft
rejection
2. Pathway: T cell receptor (TCR)-activated
signal transduction pathway
3. 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 calcineurin
5. Cn → dephosphorylates NF-AT → into
nucleus → 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
→dephosphorylation↓ → activation of NFAT↓ → suppression of the TCR-activated
signal 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-AT4
b. JNK activation → nuclear exclusion of
NF-AT4
2. Casein kinase Ia (CKIa):
binds and
phosphorylates NF-AT4→ inhibition of
NF-AT4 nuclear translocation.
3. Mitogen-activated protein kinase:extracellular
signal-regulated kinase kinase 1 (MEKK1)
→stabilizing the interaction between NF-
AT4 and CKI → suppresses NF-AT4
nuclear import
4. Glycogen synthase kinase-3 (GSK-3) :
phosphorylation and translocation of NFAT
Muscle hypertrophy
1. 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
cardiomyopathy
3. CsA: similar effect , suggesting similar
pathway of T cell activation
FINE