G-protein signaling - G-Protein alpha-s signaling cascades

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 I).

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 [1].

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 [2].

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) [3]. Phosphorylation of phosphodiesterase 4A, cAMP-specific (PDE4A) by PKA-cat (cAMP-dependent) increases PDE4A activity and catalyzes cAMP hydrolysis [4]. PKA-cat (cAMP-dependent) also phosphorylates Ryanodine receptor 1 (RYR1) and, thereby, activates a calcium (Ca2+) release channel [5].

On the other hand, phosphorylation by PKA inhibits Glycogen synthase kinase-alpha/beta (GSK3alpha/beta) activity [6], 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 [7].

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 [8].

Other cAMP-binding guanine nucleotide exchange factors Rap guanine nucleotide exchange factor (GEF) 4 and 3 (cAMP-GEFII, cAMP-GEFI) promote cell proliferation via RAP1A, member of RAS oncogene family (RAP-1A)/ v-raf murine sarcoma viral oncogene homolog B1 (B-RAF)/ MEK1(MAP2K1), MEK2(MAP2K2)/ ERK1/2 pathway and inhibit c-Raf-1 signaling [9].

References:

1. 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
2. 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
3. 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
4. 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
5. 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
6. Thomason P, Traynor D, Kay R
   Taking the plunge. Terminal differentiation in Dictyostelium. Trends in genetics : TIG 1999 Jan;15(1):15-9
7. 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
8. 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
9. 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