Adenosine A1 receptor signaling
Adenosine is a potent biological mediator
that affects numerous cell types including neuronal cells, platelets, neutrophils and
smooth muscle cells. Currently, four adenosine receptor subtypes have been identified:
A1, A2A, A2B and A3. Adenosine receptors belong to the G-protein-coupled receptor family
of cell surface receptors. Adenosine A1 receptor is a
G-protein alpha-i and
G-protein alpha-15 coupled
receptor [1].
Adenosine A1 receptor interaction with the
trimeric G-protein alpha/beta/gamma causes the exchange of
GDP to GTP bound to G-protein alpha subunits and the
dissociation of the beta/gamma heterodimers.
G-protein alpha-i inhibits activity of
several Adenylate cyclase isoforms that leads to the
decrease of cAMP level and attenuation of cAMP responsive
element binding protein 1 (CREB1) phosphorylation by Protein
kinase, cAMP-dependent, catalytic (PKA-cat (cAMP-dependent))
[2].
Phospholipase C, beta 3 (PLC-beta3)
activation is coupled with Adenosine A1
receptor signaling via both G-protein
alpha-15 and G-proteins beta/gamma subunits.
PLC-beta3 catalyzes hydrolysis of phosphoinositide
4,5-bisphosphate (PtdIns(4,5)P2) to form inositol
1,4,5-triphosphate (IP3) and 1,2-diacyl-glycerol
(DAG). The IP3 is then released
into the cytoplasm and mobilizes Ca('2+) from internal
stores, whereas DAG activates Protein kinase C delta
(PKC-delta), which, stimulates Protein kinase D1
(PKC-mu). PKC-mu plays an
important role in the Adenosine A1
receptor signaling via activation of Inhibitor of kappa light polypeptide
gene enhancer in B-cells, kinase beta (IKK-beta)/ Nuclear
factor of kappa light polypeptide gene enhancer in B-cells inhibitor
(I-kB)/ Nuclear factor of kappa light polypeptide gene
enhancer in B-cells (NF-kB) pathway [1].
DAG and
Ca(II) can also activate Protein kinase C, alpha
(PKC-alpha). PKC-alpha
regulates Phospholipase A2, group IVA (PA24A)-mediated
Arachidonic acid release independently of MAP kinase [3].
G-proteins beta/gamma subunits and the
lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate
(PtdIns(3,4,5)P3) stimulate
Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1
(PREX1) Rac-GEF activity. PREX1
is a Ras-related C3 botulinum toxin substrate 1 (Rac1)
activator [4]. Mitogen-activated protein kinase 14 (P38
MAPK) is activated by Rac1 via
Mitogen-activated protein kinase kinase kinase 4
(MEKK4(MAP3K4))/ Mitogen-activated protein kinase kinase 3
(MEK3(MAP2K3)) pathway.
The G-protein
beta/gamma heterodimers activate PI3K cat
class IB, recruiting Phosphoinositide-3-kinase, regulatory subunit 5
(PI3K reg class IB (p101)) that activates
Phosphoinositide-3-kinase, catalytic, gamma polypeptide (PI3K cat class IB
(p110-gamma)). PI3K cat class IB (p110-gamma)
converts phosphatidylinositol 4,5-biphosphate
(PtdIns(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate
(PtdIns(3,4,5)P3) [5].
PtdIns(3,4,5)P3 is a second messenger that directly binds
via pleckstrin homology (PH) domen with V-akt murine thymoma viral oncogene homolog 1
(AKT(PKB)), that activates Conserved helix-loop-helix
ubiquitous kinase
(IKK-alpha)/I-kB/NF-kB
signaling [6].
The Adenosine A1
receptor activates Mitogen-activated protein kinase 1-3
(ERK1/2) pathway via the activation of
G-protein beta/gamma
and v-src sarcoma (Schmidt-Ruppin A-2) viral
oncogene homolog (c-Src). In
turn, c-Src activates v-raf-1 murine leukemia viral oncogene
homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase
kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2))/
ERK1/2/ ELK1, member of ETS
oncogene family (ELK1) pathway via phosphorylation of
adaptor protein SHC (Src homology 2 domain containing) transforming protein
1 (Shc), and recruitment of
adaptor protein Growth factor receptor-bound protein 2
(GRB2) and Son of sevenless homolog
(SOS) [7].
References:
- Liu AM, Wong YH
G16-mediated activation of nuclear factor kappaB by the adenosine A1 receptor involves c-Src, protein kinase C, and ERK signaling.
The Journal of biological chemistry 2004 Dec 17;279(51):53196-204
- Defer N, Best-Belpomme M, Hanoune J
Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase.
American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
- Dickenson JM, Hill SJ
Transfected adenosine A1 receptor-mediated modulation of thrombin-stimulated phospholipase C and phospholipase A2 activity in CHO cells.
European journal of pharmacology 1997 Feb 19;321(1):77-86
- Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC, Hawkins PT, Stephens LR
Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits.
The Journal of biological chemistry 2005 Feb 11;280(6):4166-73
- Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer.
Annual review of cell and developmental biology 2001;17:615-75
- Igarashi J, Michel T
Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways.
The Journal of biological chemistry 2001 Sep 28;276(39):36281-8
- Schulte G, Fredholm BB
Signalling from adenosine receptors to mitogen-activated protein kinases.
Cellular signalling 2003 Sep;15(9):813-27
