Alpha-2 adrenergic receptor activation of
Alpha-2A adrenergic receptor, Alpha-2B
adrenergic receptor, and Alpha-2C-1 adrenergic
receptor participate in activation of Mitogen-activated protein kinases 1
and 3 (ERK1/2) via different ways .
Alpha-2A adrenergic receptor activates Phospholipase C
beta 3 or 2 (PLC-beta3 or
PLC-beta2) when complex Guanine nucleotide binding protein
(G protein) beta and gamma (G-protein beta/gamma) is
released from the trimeric complex with G-protein alpha-i
family (presumably by G-protein alpha-i2)
, . PLC-beta3 and
PLC-beta2 may to hydrolyze
Phosphatidylinositol-4,5-Bisphosphate (PtdIns(4,5)P2) and
produce 1,2-diacyl-glycerol (DAG) and Inositol
1,4,5-trisphosphate (IP3). IP3
activates Inositol 1,4,5-triphosphate receptor type 3 (IP3
receptor), which causes Ca('2) release from
intracellular compartments. As a result of activation of adrenergic receptor, elevated
cytosolic Ca('2) levels lead to activation of
Calmodulin/ most likely Calcium/calmodulin-dependent
protein kinase II (CaMK II)/ PTK2B protein tyrosine kinase
2 beta (Pyk2(FAK2))/ v-src sarcoma viral oncogene homolog
(c-Src)/ SHC transforming protein 1
(Shc)/ Growth factor receptor-bound protein 2
(GRB2)/ son of sevenless homolog
(SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-Ras)/ v-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1)/ Mitogen-activated protein kinase kinase 1 and 2
(MEK1 and MEK2)/
Also, activation of ERK cascade by all three
Alpha-2 adrenergic receptors is accomplished by stimulation
of Arachidonic acid production via DAG.
DAG is catalyzed by Diacylglycerol lipase alpha and beta
(DGL-alpha and DGL-beta) to
2-arachidonoylglycerol, which gets converted
by Monoglyceride lipase to Arachidonic
acid. Arachidonic acid is then converted by
Cytochrome P450 (by, for instance, Cytochrome P450 family 2 subfamily C polypeptide 8
(CYP2C8)) to 14,15-epoxyeicosatrienoic acid
(cis-14,15-Epoxyeicosatrienoic acid), which activates
c-Src. c-Src may phosphorylate matrix metalloproteinases,
for example ADAM metallopeptidase domain 12 (ADAM12).
ADAM12, in turn, cleaves Heparin-binding EGF-like growth
factor (HB-EGF) leading to transactivation of Epidermal
growth factor receptor (EGFR).
EGFR then activates Shc- and
GRB2-mediated ERK cascade
In addition, Alpha-2A and Alpha-2C-1
adrenergic receptors, after activation of
c-Src, can activate Shc/
GRB2/ SOS without
Also, all three Alpha-2 adrenergic receptors stimulate
v-akt murine thymoma viral oncogene homolog (AKT(PKB)) that
is thought to activate ERK2 and
ERK1. AKT(PKB) may act via
EGFR/ Phosphoinositide-3-kinase (PI3K)
/ PtdIns(3,4,5)P3/ possibly via
GRB2-associated binding protein 1 (GAB1) or directly/
3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)/
AKT. Alpha-2A and
Alpha-2C-1 adrenergic receptors are also able to activate
Phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha) (PI3K reg class
IA (p85-alpha)) via c-Src without
EGFR transactivation , , .
Moreover, Alpha-2B adrenergic receptor participates in
ERK activation via extracellular
Ca('2+) dependent Phospholipase A2
(cPLA2) activation, which in turn lead to
Arachidonic acid production and to the above-described
ERK cascade activation via Shc
Due to ERK activity, adrenergic receptors influence cell
growth and proliferation , . Furthermore, in nerve cells,
ERK activates Jun oncogene
(c-Jun) and participates in cell differentiation .
- Karkoulias G, Mastrogianni O, Lymperopoulos A, Paris H, Flordellis C
alpha(2)-Adrenergic receptors activate MAPK and Akt through a pathway involving arachidonic acid metabolism by cytochrome P450-dependent epoxygenase, matrix metalloproteinase activation and subtype-specific transactivation of EGFR.
Cellular signalling 2006 May;18(5):729-39
- Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ
Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase.
The Journal of biological chemistry 1997 Aug 1;272(31):19125-32
- Dorn GW 2nd, Oswald KJ, McCluskey TS, Kuhel DG, Liggett SB
Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C.
Biochemistry 1997 May 27;36(21):6415-23
- Pace AM, Faure M, Bourne HR
Gi2-mediated activation of the MAP kinase cascade.
Molecular biology of the cell 1995 Dec;6(12):1685-95
- Chen X, Resh MD
Cholesterol depletion from the plasma membrane triggers ligand-independent activation of the epidermal growth factor receptor.
The Journal of biological chemistry 2002 Dec 20;277(51):49631-7
- Cussac D, Schaak S, Gales C, Flordellis C, Denis C, Paris H
alpha(2B)-Adrenergic receptors activate MAPK and modulate proliferation of primary cultured proximal tubule cells.
American journal of physiology. Renal physiology 2002 May;282(5):F943-52
- Taraviras S, Olli-Lahdesmaki T, Lymperopoulos A, Charitonidou D, Mavroidis M, Kallio J, Scheinin M, Flordellis C
Subtype-specific neuronal differentiation of PC12 cells transfected with alpha2-adrenergic receptors.
European journal of cell biology 2002 Jun;81(6):363-74