Beta-adrenergic receptor-induced regulation of
Beta-1, Beta-2 and
Beta-3 adrenergic receptors can activate Mitogen-activated
protein kinase 1 and 3 (Erk (MAPK1/3)) phosphorylation in
v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) -
dependent and independent manner with various physiological effects, such as
cardiomyocytes hypertrophy , cell growth and development ,
proliferation , cell migration , and long-term
potentiation in neurons .
For example, Beta-2 adrenergic receptor activate GNAS
complex locus (G-protein alpha-s)/ Adenylate
cyclases, which leads to Adenosine 3',5'-cyclic phosphate
(cAMP) production. This activates Protein kinase
cAMP-dependent regulatory (PKA-reg (cAMP-dependent) and
catalytic (PKA-cat (cAMP-dependent)) subunits.
PKA-cat activates RAP1A member of RAS oncogene family
(RAP-1A)/ v-raf murine sarcoma viral oncogene homolog
B1 (B-Raf)/ Mitogen-activated
protein kinase kinase 2 and 1 (MEK2(MAP2K2) and
MEK1(MAP2K1))/ Erk . In addition, Beta adrenergic receptor-dependent
cytosolic redistribution of RAP-1A may participate, for
example, in parotid gland secretion . It is shown, that
PKA-activated Erk takes part in
cardiomyocytes hypertrophy in normal and pathological processes .
It is also known that cAMP levels may be regulated via
beta-arrestin-dependent signaling .
In addition, Beta adrenergic receptor may inhibit
Erk (stimulated by Beta
adrenergic or other receptors), possibly, via
PKA/ v-raf-1 murine leukemia viral oncogene
homolog 1 (c-Raf-1) cascade , , .
PKA-cat phosphorylation of Beta-2
adrenergic receptor leads to its activation switch from
G-protein alpha-i family to G-protein
alpha-s. G-protein alpha-i family activation
releases complex of G-protein beta/gamma, which activates
c-src tyrosine kinase (c-Src) . Moreover,
Beta-3 adrenergic receptor can
activate c-Src directly .
c-Src phosphorylates SHC transforming protein
1 (Shc) and Growth factor receptor-bound protein 2
(GRB2), activating Son of sevenless homolog
c-Raf-1 and subsequent MEK and
Erk activation , .
Additionally, cAMP activates Erk
in PKA-independent manner via Rap guanine
nucleotide exchange factor 3 (cAMP-GEFI)/ RAP2B member of
RAS oncogene family (RAP-2B) or
RAP-1A/ Phospholipase C epsilon 1
(PLC-epsilon) , , . PLC-epsilon catalyzes transformation of
Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to
1,2-diacyl-glycerol (DAG) and Inositol 1,4,5-trisphosphate
activates Inositol 1,4,5-triphosphate
receptor type 3 (IP3 receptor)-mediated
Ca('2+) release from endoplasmic reticulum , . Ca('2+) and DAG
activate RAS guanyl releasing protein 1
(CalDAG-GEFII), which triggers H-Ras
/ c-Raf-1 / MEK
/ Erk activation . It has
been shown that cAMP-GEFI-activated
Erk may participate in cell growth and development via
adhesion molecule CD44 in salivary gland cells
Beta-1 adrenergic receptor may also stimulate Rap guanine
nucleotide exchange factor (GEF) 2 (PDZ-GEF1) directly
and/or via cAMP. PDZ-GEF1/
H-Ras cascade leads to Erk
Beta-2 adrenergic receptor may activate adult cell
proliferation via some Phosphoinositide-3-kinase
(PI3K)-dependent pathway, possibly G-protein
PtdIns(3,4,5)P3/ 3-phosphoinositide dependent protein
kinase-1 (PDK (PDPK1))/ MEK
/ Erk cascade , .
Beta-2 adrenergic receptor may inhibit migration of
keratinocyte via G-protein alpha-s/ cAMP-dependent
activation of Protein phosphatase 2 (PP2A), which inhibits
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