G-Protein alpha-s signaling cascades
G-protein alpha-s coupled receptors
interact with trimeric G-protein alpha-s/ beta/gamma causing
exchange of GDP for GTP bound to G-protein alpha-s subunits,
followed by dissociation of the beta/gamma heterodimers.
G-protein alpha-s can directly stimulate
activity of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog
(c-Src) and Adenylate cyclase 1
(Adenylate cyclase type
Regulators of G-protein signaling (RGS) proteins are GTPase-activating
proteins (GAPs) that attenuate signaling by heterotrimeric G proteins. Regulator of
G-protein signaling 2, 24kDa (RGS2) directly binds with
G-protein alpha-s and selectively inhibits G
protein alpha-s function .
G-protein alpha-s activates all isoforms of
adenylate cyclases. After stimuli, Adenylate cyclase type I
increases levels of cAMP in the cell and activates Protein
kinase, cAMP-dependent (PKA) inactive complex
(PKA-reg (cAMP-dependent) - PKA-cat (cAMP-dependent)), which
results in PKA activation .
PKA regulates activity of different proteins
participating in various cell processes.
PKA-cat (cAMP-dependent) phosphorylates and stimulates
cAMP responsive element binding protein 1 (CREB1) . Phosphorylation of phosphodiesterase 4A, cAMP-specific (PDE4A)
by PKA-cat (cAMP-dependent) increases
PDE4A activity and catalyzes
cAMP hydrolysis . PKA-cat
(cAMP-dependent) also phosphorylates Ryanodine receptor 1
(RYR1) and, thereby, activates a calcium (Ca2+) release
On the other hand, phosphorylation by PKA inhibits
Glycogen synthase kinase-alpha/beta (GSK3alpha/beta)
activity , reduces the affinity of Adducin 1
(Alpha adducin) for actin complexes, and
blocks the action of Anaphase-promoting complex (APC), which
regulates mitotic progression and chromatin assembly .
Other targets for cAMP are guanine nucleotide exchange
factors for small GTPases. cAMP binds guanine nucleotide
exchange factor Rap guanine nucleotide exchange factor (GEF) 2
(PDZ-GEF1) and activates Mitogen-activated protein kinase
kinases 1 and 2 (MEK1(MAP2K1),
MEK2(MAP2K2))/ Mitogen-activated protein kinases 1-3
(ERK1/2) pathway via v-Ha-ras Harvey rat sarcoma viral
oncogene homolog (H-RAS)- v-raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1) regulation .
Other cAMP-binding guanine nucleotide exchange factors Rap guanine nucleotide exchange
factor (GEF) 4 and 3
cAMP-GEFI) promote cell proliferation via
RAP1A, member of RAS oncogene family
(RAP-1A)/ v-raf murine sarcoma viral oncogene homolog B1
MEK2(MAP2K2)/ ERK1/2 pathway
and inhibit c-Raf-1 signaling .
- Roy AA, Lemberg KE, Chidiac P
Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions.
Molecular pharmacology 2003 Sep;64(3):587-93
- 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
- Don J, Stelzer G
The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis.
Molecular and cellular endocrinology 2002 Feb 22;187(1-2):115-24
- Abrahamsen H, Baillie G, Ngai J, Vang T, Nika K, Ruppelt A, Mustelin T, Zaccolo M, Houslay M, Tasken K
TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling.
Journal of immunology (Baltimore, Md. : 1950) 2004 Oct 15;173(8):4847-58
- Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka T, Obayashi M, Ohkusa T, Kohno M, Matsuzaki M
FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.
Circulation 2003 Jan 28;107(3):477-84
- Thomason P, Traynor D, Kay R
Taking the plunge. Terminal differentiation in Dictyostelium.
Trends in genetics : TIG 1999 Jan;15(1):15-9
- Harkness TA, Shea KA, Legrand C, Brahmania M, Davies GF
A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast.
Genetics 2004 Oct;168(2):759-74
- Pham N, Rotin D
Nedd4 regulates ubiquitination and stability of the guanine-nucleotide exchange factor CNrasGEF.
The Journal of biological chemistry 2001 Dec 14;276(50):46995-7003
- Fujita T, Meguro T, Fukuyama R, Nakamuta H, Koida M
New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells. Checkpoint of modulation by cyclic AMP.
The Journal of biological chemistry 2002 Jun 21;277(25):22191-200