G-Beta Gamma Signaling
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G-Beta Gamma Signaling

G-proteins (Guanine Nucleotide-Binding Proteins) are heterotrimeric proteins that mediate signal transduction between many membrane-bound receptors and intracellular effectors. Traditionally, activation of heterotrimeric G-proteins is accomplished exclusively by the action of GPCRs (G-Protein Coupled Receptors), Seven transmembrane-spanning proteins that typically reside in the plasma membrane. G-proteins consist of Alpha, Beta and Gamma subunits, and each is involved in signaling to distinct effectors. There are 20 different mammalian G-Alpha subunits (depending on alternative splicing) and 6 G-Beta and 14 G-Gamma subtypes. The G-Beta-subunit of heterotrimeric G-proteins has a Beta-propeller structure containing seven WD-40 repeats. The Gamma-subunit interacts with the G-Beta -subunit through an N-terminal coiled coil and makes extensive contacts along the base of the G-Beta subunit. The G-BetaGamma-dimer binds to a hydrophobic pocket present in G-Alpha-GDP. GTP binding to G-Alpha removes the hydrophobic pocket and reduces the affinity of G-Alpha for G-BetaGamma. Subsequently G-Alpha-GTP dissociates from G-BetaGamma and from the receptor. Both G-Alpha-GTP and G-BetaGamma are then free to activate downstream effectors (Ref.1 & 2).

The BetaGamma-complex of mammalian G-Proteins is assembled from a repertoire of 5 G-proteins Beta-subunits (GNB1 (G-Beta1), GNB2 (G-Beta2), GNB3 (G-Beta3), GNB4 (G-Beta4) and GNB5 (G-Beta5)) and 12 Gamma-subunits (GNGT1 (G-Gamma1), GNGT2 (G-Gamma14), GNG2 (G-Gamma2), GNG3 (G-Gamma3), GNG4 (G-Gamma4), GNG5 (G-Gamma5), GNG7 (G-Gamma7), GNG8 (G-Gamma8), GNG10 (G-Gamma10), GNG11 (G-Gamma11), GNG12 (G-Gamma12) and GNG13 (G-Gamma13)). While Beta1- to Beta4-subunits form a tight complex with Gamma-subunits, the Beta5-subunit interaction with Gamma-subunits is comparably weak. The Beta5-subunit is an exception in that it can also be found in a complex with a subgroup of RGS proteins. The BetaGamma-complex was initially regarded as a more passive partner of the G-proteins Alpha-subunit. However, it has become clear that BetaGamma-complexes freed from the G-proteins Alpha-subunit can regulate various effectors. G-BetaGamma-mediated signaling occurs through interactions with a variety of molecules, including enzymes, ion channels, and small G-proteins. The effectors directly regulated by G-BetaGamma include PLC (Phospholipase-C), KCn (Potassium channels) channels, AC (Adenyl Cyclase), and PI3K (Phosphatidylinositol 3-Kinase). Although each of these effectors exists as multiple isoforms, only specific isoforms are regulated by G-BetaGamma. PLC is one of the major effector of G-BetaGamma. Although the G-BetaGamma dimer interacts with PLC-Beta1, PLC-Beta2, and PLC-Beta3, it exhibits a high affinity only for PLC-Beta2. The activation of PLC-Beta2 by G-Beta Gamma in response to ligation of the LHR (Luteinizing Hormone Receptor), V2 Vasopressin Receptor, m2 Muscarinic Acetylcholine Receptor are known. G-Beta Gamma also activates PLC-Gamma indirectly through the activation of BTK (Bruton’s Tyrosine Kinase). The pleckstrin homology domain of BTK interacts with the G-BetaGamma leading to increased  kinase activity and activation of PLC-Gamma. Activation of mammalian Phosphoinositide-specific PLC results in the hydrolysis of PIP2 (Phosphatidylinositol 4,5-bisphosphate) to release the second messengers DAG (1,2-Diacylglycerol) and IP3 (Inositol Trisphosphate). IP3 diffuses through the Cytosol and releases stored Ca2+ (Calcium) ions from the ER (Endoplasmic Reticulum). DAG activates PKC (Protein Kinase-C), which in turn lead to phosphorylation of various substrate proteins that are involved in an array of cellular events. PKC activates the ERK (Extracellular Signal-Regulated Kinase) cascade, including direct phosphorylation of either MEK (MAPK /ERK Kinase) or Raf1 (v-Raf1 Murine Leukemia Viral Oncogene Homolog-1) (Ref.3 & 4).

Another important substrate of G-BetaGamma is PI3K. PI3K phosphorylate PIP2 to produce PIP3 (Phosphatidylinositol-3,4,5-Triphosphate) at the inner leaflet of the Plasma membrane, which are the major Phosphoinositides in the mammalian systems. The binding of PIP3 to the PH domain anchors Akt to the plasma membrane and allows its phosphorylation and activation by PDK-1 (Phosphoinositide-Dependent Kinase-1). Activated Akt then phosphorylates several substrates and take part in cell survival and cell proliferation. G-BetaGamma can also regulate cAMP activation by activating or inhibiting different AC (Adenylate Cyclase) isoforms. The traditional role of G-BetaGamma subunits, released following activation of G-AlphaI proteins, is to bind active G-AlphaS-GTP species, reducing their activity and leading to decreased cAMP (Cyclic Adenosine 3,5-monophosphate) levels. However, G-BetaGamma subunits of the Pertussis toxin sensitive G-AlphaI proteins can enhance the effect of G-AlphaS on type II and IV AC but can inhibit G-AlphaS-stimulated type I AC . The other three G-AlphaS-stimulated AC (type III, V and VI) appear not to be modulated by the G-BetaGammasubunits. G-BetaGamma subunits also transactivate the EGFR (Epidermal Growth Factor Receptor) indirectly by stimulating the shedding of ProHB- EGF through the actions of metalloproteases. Activation of the EGFR then leads to activation of the Ras-Raf-MAPK (Mitogen-Activated Protein Kinase) pathway. One major signaling role for G-BetaGamma is the management of MAPK cascades, which allows communication between G-BetaGamma and the nucleus. G-BetaGamma activates c-Src to regulate MAPK cascade activation. Src activates ERKs via Ras. Src can trigger SHC phosphorylation and subsequent activation of the Ras exchanger SOS (Son of Sevenless). Src can also activate Ras through the transactivation of the EGF receptor and related receptors following stimulation of GPCRs via G-BetaGamma subunits and the assembly of multiprotein complexes of Dynamin-2 and Caveolin-1 at Clathrin-dependent sites of endocytosis. G-BetaGamma also regulates N-type Ca2+ channels. G-BetaGamma subunits also directly bind to and activate a class of K+ channels called GIRKs. G-BetaGamma also binds PAK1 (p21/CDC42/Rac1-Activated Kinase-1) and, via PAK-associated PIX-Alpha, activates CDC42 (Cell division Cycle-42), which in turn activates PAK1. This G-BetaGamma-PAK1/PIX-Alpha/CDC42 pathway is essential for the localization of F-Actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes (Ref.5, 6 & 7).

G-Beta Gamma also interacts with several nuclear proteins such as HDAC5 (Histone Deacetylase-5), MEF2C (MADS Box Transcription Enhancer Factor-2 Polypeptide-C) and ICAM1 (Intercellular Adhesion Molecule-1). G-BetaGamma interacts with the C-terminal domain of HDAC5 and has an inhibitory effect on HDAC5 function. G-BetaGamma also play a role in the induction of ICAM-1 transcription by Thrombin stimulation of PAR1 (Protease-Activated Receptor-1) in endothelial cells. Accordingly, G-BetaGamma is thought to play an important role in cell proliferation. One class of protein kinase that binds G-BetaGamma subunits is called GRKs (G-protein Receptor Kinases). These Kinases phosphorylate G-proteins-coupled receptors that are occupied by ligand and thereby mediate one form of receptor desensitization. It now appears that G-BetaGamma subunits play a key role in this process.  G-BetaGamma also interacts with Ubiquitin-related protein PLIC1 and the Glucocorticoid receptor. The association with Glucocorticoid Receptor correlates with nuclear import of G-Beta Gamma upon Glucocorticoid stimulation and plasma membrane association of the Glucocorticoid receptor upon activation of the somatostatin GPCR. G-BetaGamma was found to suppress glucocorticoid-dependent transcriptional activity. Putative G-BetaGamma-effectors recently identified include PKD (Protein Kinase-D), Tubulin, KSR-1, Tsk protein kinase and Calmodulin. G-BetaGamma subunits have potential as a target for therapeutic treatment of a number of diseases. The G-Proteins regulate important cellular components, such as metabolic enzymes, ion channels, and the transcriptional machinery. The resulting alterations in cellular behavior and function are manifested in many critical systemic functions, including embryonic development, learning and memory, and organismal homeostasis. This results in the propagation of regulated activities through increasingly complex layers of organization to serve as the basis of integration at the systemic level (Ref.8, 9 & 10 ).