G-AlphaQ Signaling
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G-AlphaQ Signaling
GPCR (G-Protein-Coupled Receptors) constitute a large and diverse family of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. They are among the largest and most diverse protein families in mammalian genomes. Also termed Serpentine receptors, GPCRs are polytopic membrane proteins that share a common structure with seven transmembrane segments, but sequence similarity is minimal among the most distant GPCRs. GPCRs recognize a variety of ligands and stimuli including Peptide and non-peptide Hormones and Neurotransmitters, Chemokines, Prostanoids and Proteinases, Biogenic amines, Nucleosides, Lipids, Growth Factors, Odorant molecules and Light. These receptors affect the generation of small molecules that act as intracellular mediators or second messengers, and can regulate a highly interconnected network of biochemical routes. GPCRs transduce extracellular stimuli to give intracellular signals through interaction of their intracellular domains with heterotrimeric G-Proteins play important roles in determining the specificity and temporal characteristics of the cellular responses to signals. They are made up of Alpha, Beta, and Gamma subunits. There are 20 different mammalian G-Alpha subunits (depending on alternative splicing) and 6 G-Beta and 14 G-Gamma subtypes. G-Proteins are inactive in the GDP-bound, heterotrimeric state and are activated by receptor-catalyzed guanine nucleotide exchange resulting in GTP binding to the Alpha subunit. GTP binding leads to dissociation of G-Alpha-GTP from G-BetaGamma subunits and activation of downstream effectors by both G-Alpha-GTP and free G-BetaGamma subunits.G-Proteins deactivation is rate-limiting for turnoff of the cellular response and occurs when the G-Alpha subunit hydrolyzes GTP to GDP (Ref.1 & 2).

On the basis of sequence similarity, the G-Alpha subunits have been divided into four families: G-AlphaI/O, G-AlphaS, G-AlphaQ/11, and G-Alpha12/13. These four broad G-Protein families transduce signals from a very large number of extracellular agents. Each family consists of various members that often show very specific expression patterns. Members of one family are structurally similar and often share some of their functional properties. G-AlphaQ/11 family of G proteins consists of 4 members: GNAQ, GNA11, GNA14 and GNA15/16 (GNA15 being the murine, GNA16 the human ortholog). The Alpha-subunits of GQ and G11 are almost ubiquitously expressed while the other members of this family like G-Alpha14 and G-Alpha15/16 show a rather restricted expression pattern. Receptors that are able to couple to the GQ/G11 family do not appear to discriminate between GQ and G11. While the importance of GQ and G11 in various biological processes has been well established, the roles of G-Alpha14 and G-Alpha15/16, which show very specific expression patterns, are not clear. The G-AlphaQ pathway is a classical pathway in which G-AlphaQ protein transduces signals from cell surface receptors that are activated by hormones such as Angiotensin-II, Endothelin-1, Catecholamines, and Prostaglandi F2-Alpha to regulate diverse physiological functions. The most well characterized effector of G-AlphaQ is PLC-Beta(Phospholipase-C-Beta), the activation of which leads to increased hydrolysis of PIP2 (Phosphatidylinositol 4,5-bisphosphate) to produce the intracellular messengers IP3 (Inositol trisphosphate) and DAG (Diacylglycerol). IP3, which accumulates rapidly and transiently, binds to intracellular receptors, IP3R (IP3 Receptor) in the intracellular stores like ER (Endoplasmic Reticulum) and activates Ca2+ release from the ER lumen to the cytoplasm, generating complex cytoplasmic Ca2+ concentration signals including temporal oscillations and propagating waves. Ca2+ release activates Calm (Calmodulin) which further activates Caln (Calcineurin), CamKKs (Calcium/Calmodulin-Dependent Protein Kinase Kinases)  and CamKs (Calcium/Calmodulin-Dependent Protein Kinases) (CamK4 and CamK2). Caln facilitates NFAT (Nuclear Factor of Activated T-Cells) translocation to the nucleus, a process that is quite essential for axonal growth. Ca2+ release may also activate PKC (Protein Kinase-C). In many cell types, the release of intracellular Calcium activates the store-operated Calcium channels at the cell surface to allow the inflow of extracellular calcium. PIP2 also forms DAG, which recruits PKC to the membrane and activates it. PKC, once activated activates Raf, which in turn activates ERKs (Extracellular Signal-Regulated Kinases) via MEKs (MAPK/ERK Kinases). Activated ERK then enter the nucleus and activates transcription factor Elk1,which stimulates transcription. It binds to purine-rich DNA sequences and can form a ternary complex with the SRF (Serum Response Factor) and the Ets and SRF motifs of the Fos serum response element. G-AlphaQ, working through PKC and possibly directly, also appears to regulate various isoforms of PLD (Phospholipase-D). PLD catalyze the hydrolysis of PC (Phosphatidylcholine) to produce PA (Phosphatidic Acid) and Choline, which take part in cell activation. Activation of this canonical PLC-Beta pathway by G-AlphaQ accounts for most of the pleiotropic effects of G-AlphaQ-coupled receptors. Direct binding of G-AlphaQ to BTK (Bruton Agammaglobulinemia Tyrosine Kinase) has been shown to increase BTK kinase activity. Activated BTK phosphorylates PLC-Gamma2, which further take part in IP3 and DAG production (Ref.3, 4 & 5).

G-AlphaQ also activates the transcription factor NF-KappaB (Nuclear Factor-KappaB) through PYK2 (Proline-Rich Tyrosine Kinase-2). PYK2 activated by G-AlphaQ, leads to the stimulation of PI3KBeta (Phosphoinositide 3-Kinase-Beta). PI3K phosphorylate membrane bound PIP2 to generate PIP3 (Phosphatidylinositol-3,4,5-Triphosphate).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 leads to the activation of IKKs (I-KappaB-Kinases), and finally nuclear factor NF-KappaB-dependent transcription. The protein tyrosine kinase PYK2 also acts as an upstream regulator of MAPK (Mitogen-Activated Protein Kinase) cascades in response to numerous extracellular signals. PYK2 activates SHC through tyrosine phosphorylation. The resultant SHC-GRB2 (Growth Factor Receptor-Bound Protein-2)-SOS (Son of Sevenless) Complex stimulates Ras, which leads to the sequential activation of Raf, MEKs and ERKs. PYK2-induced activation of Src is necessary for phosphorylation of SHC and p130CAS (Crk-Associated Substrate-P130) and their association with GRB2 and Crk (v-Crk Avian Sarcoma Virus Ct10 Oncogene Homolog), respectively, and for the activation of ERKs and JNK cascades. TRPC6 (Transient Receptor Potential Canonical-6), voltage-gated cation channel that play critical roles in regulating intracellular calcium levels, is also potently activated by G-AlphaQ-coupled GPCR (Ref.6 & 7). Recent evidence suggests that cell surface receptors linked to the GN-AlphaQ family of heterotrimeric G-proteins can also activate signaling routes that are dependent on the functional activity of Rho. Receptors transmitting signals through G-AlphaQ can promote Rho activation, thereby initiating the activity of intracellular pathways controlled by Rho. G-AlphaQ and G-AlphaQ-coupled receptors can potently stimulate the Rho-related GTPase Rac1. The molecular mechanism by which G-AlphaQ stimulates these RhoGTPases, however, is yet to be fully defined. RhoGEFs containing an RGS domain are found to be good candidates to mediate G-AlphaQ function. G-AlphaQ may interact with RhoGEFs and activate Rho, which may further activate Rho Kinase and take part in Actin reorganization. G-AlphaQ also activates GSK3Beta (Glycogen synthase kinase-3-Beta) via Csk (C-terminal Src kinase). GSK3, a serine/threonine protein kinase, further phosphorylates and inactivates Glycogen Synthase and affects Glycogen metabolism (Ref.8 & 9).

Recently, the intracellular RGS (Regulator of G-protein Signalling) proteins have been discovered to serve additional, mostly negative, modulatory roles in G-AlphaQ-mediated signal transduction. RGS proteins directly inhibit the interaction between G-AlphaQ and PLC-Beta by competitively binding to G-AlphaQ. By virtue of their GAP effects on G-AlphaQ, many RGS proteins can inhibit PLC-Beta activity. In addition, a number of RGS proteins, including RGS2, RGS3, RGS4 and RGS10, can block PLC-Beta activation by GTP GammaS-activated G-AlphaQ, indicating that they have the capacity to inhibit signaling through this effector without deactivating the G-Protein. RGS4 can directly interact with both PLC-Beta and G-AlphaQ, and PLC-Beta can bind to a complex of RGS4 and G-AlphaQ, suggesting that RGS4 may remain anchored to the G-AlphaQ, G-Beta-Gamma, PLC-Beta signaling complex in order to rapidly shut down the activated G-AlphaQ signal. GRKs (G-protein-coupled Receptor Kinases) also inhibit G-AlphaQ signaling. GRKs contain a regulator of RGS-like domain located at the N terminus (GRK-Nter) of their sequence. This domain is present in all the GRK subtypes, but the RGS-like domain of GRK2 was found to be functionally active, as it is able to interact selectively with G-AlphaQ and to inhibit G-AlphaQ -dependent signaling. G-AlphaQ and its coupled receptors play an important role in regulating gene expression, hypertrophy, and normal and cancerous growth. G-AlphaQ-coupled signaling cascades may also be important effector pathways mediating Podocyte injury and that modulating the activity of these pathways might be a useful strategy for treating glomerular disease processes (Ref.1, 10 & 11).