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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