Disease relevance of Gnaq

• MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq [1].
• We then assessed the effect of overexpressing wild-type Galphaq (WT-Galphaq) or a constitutively active Galphaq mutant (Q209L-Galphaq) by using an adenovirus expression vector [2].
• Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes [3].
• These alpha subunits are related to members of the Gq class and share certain sequence characteristics with G alpha q, G alpha 11, and G alpha 16, such as the absence of a pertussis toxin ADP-ribosylation site [4].
• Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways [5].
• Deletion of Gnaq in the immune system leads to the development of a multi-organ autoimmune disease in a B cell dependent manner [6].

Psychiatry related information on Gnaq

• Heterotrimeric G proteins of the Gq/11 family are crucial for the induction of maternal behavior in mice [7].
• The expression pattern of the Gq subunit in adult antennae was associated with the olfactory sensilla suggesting a specific role in olfaction [8].

High impact information on Gnaq

• Interactions between Gq and Kit receptor tyrosine kinase signaling can mediate coordinate or independent control of skin and hair color [9].
• A new study shows that three such strains carry activating mutations in the genes encoding the G-protein subunits Galphaq or Galpha11, resulting in more pigment cell precursors and an excess of dermally retained pigment cells at birth [10].
• Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src [11].
• We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress [12].
• However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families [3].

Chemical compound and disease context of Gnaq

• Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy [3].
• Both MLC phosphorylation and shape change induced through G12/G13 in the absence of Galphaq were inhibited by the C3 exoenzyme from Clostridium botulinum, by the Rho-kinase inhibitor Y-27632 and by cAMP-analogue Sp-5,6-DCl-cBIMPS [13].
• Gq signaling is required for allergen-induced pulmonary eosinophilia [14].
• The response was blocked by inactivation of pertussis toxin-sensitive, heterotrimeric guanine nucleotide-binding proteins (G proteins) and by depletion of Galphaq and Galphao [15].
• Pasteurella multocida toxin facilitates inositol phosphate formation by bombesin through tyrosine phosphorylation of G alpha q [16].

Biological context of Gnaq

• However, ADP caused Akt phosphorylation in Galphaq- and P2Y1-deficient platelets, which was completely blocked by AR-C69931MX [17].
• Phospholipase C-beta1 directly accelerates GTP hydrolysis by Galphaq and acceleration is inhibited by Gbeta gamma subunits [18].
• Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially Gq, whose alpha subunit activates phospholipase Cbeta (PLCbeta) [5].
• In transgenic mice with cardiac G alpha q overexpression, heart failure and increased cardiomyocyte apoptosis develop during the peripartal period [19].
• Our findings suggest that an Akt-mediated cell survival pathway is compromised by the diminished availability of PIP2 elicited by pathological levels of Gq activity [19].
• Gnaq plays a role in generating Calcium flux and cell migration of neutrophils and dendritic cells, in response to select chemokine receptor ligands [20].

Anatomical context of Gnaq

• In cardiac myocytes derived from embryonic stem cells in culture, homozygous disruption of MEKK1 selectively impaired c-Jun N-terminal kinase activity in the absence or presence of phenlyephrine, a Galphaq-dependent agonist [1].
• G alpha-q/11 protein plays a key role in insulin-induced glucose transport in 3T3-L1 adipocytes [2].
• Signaling evoked by other receptors coupled by Gq class alpha subunits appeared normal in Galpha15(-/-) macrophages [21].
• Regulation of serum response factor (SRF)-mediated gene transcription by G protein subunits and G protein-coupled receptors was investigated in transfected NIH3T3 cells and in a cell line that was derived from mice lacking Galphaq and Galpha11 [22].
• We investigated the involvement of G12 or G13 in stress fiber formation induced through a variety of Gq/G11-coupled receptors [23].

Associations of Gnaq with chemical compounds

• We also found that the type 1 muscarinic receptor (m1R) and alpha1-adrenergic receptor (AR)-mediated SRF activation is exclusively dependent on Galphaq/11, while the receptors for thrombin, lysophosphatidic acid (LPA), thromboxane A2, and endothelin can activate SRF in the absence of Galphaq/11 [22].
• And RGS12, but not other RGS proteins, blocked thrombin- and LPA-mediated SRF activation in the Galphaq/11-deficient cells [22].
• Stress fiber assembly induced through the muscarinic M1 and the metabotropic glutamate subtype 1alpha receptors was dependent on Gq/G11 proteins [23].
• On the contrary, receptors including beta2- and alpha2-ARs, m2R, the dopamine receptors type 1 and 2, angiotensin receptors types 1 and 2, and interleukin-8 receptor could not activate SRF in the presence or absence of Galphaq/11, suggesting that these receptors cannot couple to endogenous G proteins of the G12 or Gq classes [22].
• Akt-mediated cardiomyocyte survival pathways are compromised by G alpha q-induced phosphoinositide 4,5-bisphosphate depletion [19].

Physical interactions of Gnaq

• Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA [24].
• 6. Our results show that, in mouse duodenal myocytes, acetylcholine-induced release of Ca2+ from intracellular stores is mediated through activation of muscarinic M3 receptors which couple with a Gq protein to activate a phosphatidylinositol-specific phospholipase C [25].
• In the hypertrophied myocardium, the interruption of the transduction from Galphaq-protein coupled receptors to downstream effectors may be due to the down-regulation of caveolin-3 expression [26].
• Stimulation of rat vascular smooth muscle cell G alphaq-coupled P2Y nucleotide receptors with UTP induces luciferase transcription from a sensitive and specific NF kappaB dependent promoter [27].
• These findings are consistent with strontium activation of a novel Galphaq-coupled extracellular cation-sensing receptor in osteoblasts with distinct cation specificity [28].

Co-localisations of Gnaq

• By double immunofluorescence, Galphaq/Galpha11 was extensively colocalized with metabotropic glutamate receptor mGluR1alpha in dendritic spines of PCs and with mGluR5 in those of hippocampal pyramidal cells [29].

Regulatory relationships of Gnaq

• We now use a moderately stable complex of R183C Galphaq bound to GTP to show that PLC-beta1 acts directly as a GTPase-activating protein (GAP) for isolated Galphaq in a membrane-free system [18].
• Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class alpha subunits may suppress abnormalities in Galpha15-deficient mice [21].
• G alpha 11 and G alpha q are ubiquitously expressed among murine tissues but G alpha 14 is predominantly expressed in spleen, lung, kidney, and testis whereas G alpha 15 is primarily restricted to hematopoietic lineages [4].
• Biochemical studies indicate that the M1 receptor plays a significant role in regulating G alpha q-mediated signal transduction in the hippocampus and cortex [30].
• In this study, we investigated the effect of constitutive activation of Gq signaling on GnRH-induced signaling and LH secretion [31].

Other interactions of Gnaq

• Here, we show that endogenous cardiac MAPK/ERK kinase kinase-1 (MEKK1)/(MAP3K1), a mitogen-activated protein kinase kinase kinase, is activated by heart-restricted overexpression of Galphaq in mice [1].
• However, the possible contribution of Gq/G11 to the regulation of RhoA activity via GPCRs is controversial [32].
• Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation [33].
• We inhibited endogenous Galphaq function by single cell microinjection of anti-Galphaq/11 antibody or RGS2 protein (a GAP protein for Galphaq), followed by immunostaining to assess GLUT4 translocation in 3T3-L1 adipocytes [2].
• Rho activation induced by receptor agonists via Gq/G11 occurs with lower potency than Rho activation via G12/G13 [32].

Analytical, diagnostic and therapeutic context of Gnaq

• Western blot analysis showed that these cells express three of the four Gq class subunits, Galphaq, Galpha11, and Galpha14 but not Galpha15 [34].
• Both G11 KO and Gq KO male mice released LH in response to Buserelin (2 microg/100 microl of vehicle; 363 +/- 53 pg/25 microl and 749 +/- 50 pg/25 microl 1 h after treatment, respectively) [35].
• There was no significant difference in Buserelin stimulated estradiol production in the female Gq KO mice compared with control groups of mice [35].
• Here we examined the expression and localization of Gq protein alpha subunits in the adult mouse brain by in situ hybridization and immunohistochemistry [29].
• To analyze the selectivity of delta receptor subtypes to regulate different classes of G proteins, the expression of the alpha-subunits of Gi2, Gi3, Go1, Go2, Gq and G11 transducer proteins was reduced by administration of oligodeoxynucleotides (ODNs) complementary to sequences in their respective mRNAs [36].

References