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Functional Domains of Neuron-to-Astrocyte Gq GPCR Communication
No full textThe physiological role of astrocytic Gq-protein coupled receptors (Gq GPCRs) has now drawn more attention in the field of neuroscience, as it is now clear that astrocytes sense neuronal signals through activation of their Gq GPCRs. Astrocytes are thus considered excitable and their role in synaptic transmission is under intense investigation. Interestingly, in basal conditions without any user-evoked stimulation, astrocytes exhibit spontaneous Gq GPCR activity driven by mechanisms that still remain mysterious. Understanding the mechanisms underlying these astrocytic Gq GPCR signaling domains in physiological conditions will certainly benefit our knowledge regarding neuron-to-astrocyte communication. Therefore, the main goal of this dissertation is to study the underlying mechanisms of astrocytic Gq GPCR signaling domains in two parts: 1) To identify the factors governing spontaneous astrocytic Gq GPCR activity, and 2) To identify the lowest threshold of neuronal action potential-mediated synaptic transmission capable of evoking an astrocytic Gq GPCR response, and then to determine if the response occurs as a microdomain or a whole-cell event. In Chapter 2, we demonstrate that spontaneous astrocytic Gq GPCR signaling domains are driven by mechanisms unrelated to action potential-triggered neurotransmitter release, but are dependent on spontaneous miniature neurotransmitter release. It also appears that multiple types of astrocytic Gq GPCRs play essential roles in the generation of spontaneous Gq GPCR activity. In Chapter 3, our results suggest that astrocytes respond to neuronal afferent stimulation at intensities much lower than previously described. Moreover, the evoked Gq GPCR domains are qualitatively different from the spontaneous ones. Consistent with the findings from Chapter 2, the evoked events appear to involve multiple types of astrocytic Gq GPCRs. These data suggest that astrocytes respond to neuronal activity in a manner much more sensitive than previously thought. We also explored the role of beta-Arrestin2 in regulating two forms of synaptic plasticity-long-term potentiation (LTP) and long-term depression (LTD). In Chapter 4, we report normal LTP, but a markedly impaired LTD in beta-Arrestin2 knockout mice, suggesting a novel role of beta-Arrestin2 in cellular mechanisms of learning and memory. This finding could potentially provide a base for developing treatments for dementia-related disorders such as Alzheimer's disease
ALMA Observations of the GQ Lup System
No full textWe present ALMA band 7 line and continuum observations of the GQ Lup system, a young Sun-like star with a substellar mass companion at 100 AU separation. We characterize the disk around the primary, constrain the stellar mass using the disk Keplerian rotation, and place an upper limit on the mass of a disk around the companion. We discuss possible formation mechanisms for the companion.David Wilner, Luca Ricci, Sean Andrews, Leonardo Testi, Adam Kraus, Kaitlin Kratter, Yu Dai, Gregory Hercze
Gq Protein-Coupled Membrane-Initiated Estrogen Signaling Rapidly Excites Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus in Female Mice
No full textCRH neurons in the hypothalamic paraventricular nucleus (PVN) play a central role in regulating the hypothalamus-pituitary-adrenal (HPA) axis and are directly influenced by 17β-estradiol (E2). Although compelling evidence has suggested the existence of membrane-associated estrogen receptors (mERs) in hypothalamic and other central nervous system neurons, it remains unknown whether E2 impacts CRH neuronal excitability through this mechanism. The purpose of the current study is to examine the existence and function of mER signaling in PVN CRH neurons. Whole-cell recordings were made from CRH neurons identified by Alexa Fluor 594 labeling and post hoc immunostaining in ovariectomized female mice. E2 (100nM) rapidly suppressed the M-current (a voltage-dependent K(+) current) and potentiated glutamatergic excitatory postsynaptic currents. The putative Gq-coupled mER (Gq-mER) characterized in hypothalamic proopiomelanocortin neurons initiates a phospholipase C-protein kinase C-protein kinase A pathway; therefore, we examined the involvement of this pathway using selective inhibitors. Indeed, the ER antagonist ICI 182780 and inhibitors of Gq-phospholipase C-protein kinase C-protein kinase A blocked E2's actions, suggesting dependence on the Gq-mER. Furthermore, STX, a selective ligand for the Gq-mER, mimicked E2's actions. Finally, to examine the in vivo effect of Gq-mER activation, E2 or STX injection increased c-fos expression in CRH neurons in the PVN, suggesting CRH neuronal activation. This corresponded to an increase in plasma corticosterone. We conclude that the Gq-mER plays a critical role in the rapid regulation of CRH neuronal activity and the HPA axis. Our findings provide a potential underlying mechanism for E2's involvement in the pathophysiology of HPA-associated mood disorders.Peer reviewe
Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP
No full textSummaryUveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11
ALMA Measurements of Circumstellar Material in the GQ Lup System
No full textWe present ALMA observations of the GQ Lup system, a young Sun-like star with a substellar mass companion in a wide-separation orbit. These observations of 870 micron continuum and CO J=3-2 line emission with beam 0.3 arcsec (45 AU) resolve the disk of dust and gas surrounding the primary star, GQ Lup A, and provide deep limits on any circumplanetary disk surrounding the companion, GQ Lup b. The 3 sigma upper limit on the 870 micron flux density of < 0.15 mJy implies an upper limit on the GQ Lup b disk mass of about 0.04 solar masses for standard assumptions about optically thin dust emission. Given the non-detection of a circumplanetary disk around GQ Lup b, and other similar systems observed by ALMA, we discuss implications for formation mechanisms of wide-separation substellar companions
ALMA MEASUREMENTS OF CIRCUMSTELLAR MATERIAL IN THE GQ LUP SYSTEM
No full textWe present Atacama Large Millimeter/submillimeter Array observations of the GQ Lup system, a young Sun-like star with a substellar-mass companion in a wide-separation orbit. These observations of 870 mu m continuum and CO J = 3-2 line emission with beam size similar to 0."3 (similar to 45 au) resolve the disk of dust and gas surrounding the primary star, GQ Lup A, and provide deep limits on any circumplanetary disk surrounding the companion, GQ Lup b. The circumprimary dust disk is compact with an FWHM of 59 +/- 12 au, while the gas has a larger extent with a characteristic radius of 46.5 +/- 1.8 au. By forward-modeling the velocity field of the circumprimary disk based on the CO emission, we constrain the mass of GQ Lup. A to be M-* = (1.03 +/- 0.05) * (d/156 pc) M-circle dot, where d is a known distance, and determine that we view the disk at an inclination angle of 60 degrees 5 +/- 0 degrees 5 and a position angle of 346 degrees +/- 1 degrees. The 3s upper limit on the 870 mu m flux density of any circumplanetary disk associated with GQ Lup b of <0.15 mJy implies an upper limit on the dust disk mass of <0.04M(circle dot) for standard assumptions about optically thin emission. We discuss proposed mechanisms for the formation of wide-separation substellar companions given the non-detection of circumplanetary disks around GQ Lup b and other similar systems.National Science Foundation Graduate Research Fellowship [DGE1144152]; NRAO Student Observing SupportSCI(E)ARTICLE183
Endothelin Type B Receptor–Induced Sustained Ca2+ Influx Involves Gq/11/Phospholipase C–Independent, p38 Mitogen-Activated Protein Kinase–Dependent Activation of Na+/H+ Exchanger
No full textThe mechanism for sustained Ca2+ influx activated by G protein-coupled receptors was examined. In Chinese hamster ovary cells expressing recombinant human endothelin type B receptor (ETBR) and endogenous P2Y receptor (P2Y-R), endothelin-1 elicited a sustained Ca2+ influx depending on Gq/11 protein, phospholipase C (PLC), Na+/H+ exchanger (NHE) and p38 mitogen-activated protein kinase (p38MAPK), whereas P2Y-R-induced sustained Ca2+ influx was negligible. Functional study showed that NHE activation by ETBR was mediated via p38MAPK but not Gq/11/PLC, while that by P2Y-R involves only Gq/11/PLC/p38MAPK. These results suggest that Gq/11/PLC-independent NHE activation via p38MAPK plays an important role in ETBR-mediated sustained Ca2+ influx
GQ corrections in the circuit theory of quantum transport
No full textWe develop a finite-element technique that allows one to evaluate correction of the order of GQ to various transport characteristics of arbitrary nanostructures. Common examples of such corrections are the weak-localization effect on conductance and universal conductance fluctuations. Our approach, however, is not restricted to conductance only. It allows one in the same manner to evaluate corrections to the noise characteristics, superconducting properties, strongly nonequilibrium transport, and transmission distribution. To enable such functionality, we consider Green’s functions of arbitrary matrix structure. We derive a finite-element technique from Cooperon and diffuson ladders for these Green’s functions. The derivation is supplemented with application examples. Those include transitions between ensembles and the Aharonov-Bohm effect.Kavli Institute of NanoscienceApplied Science
Gq/G11 oncogenic mutations promote PD-L1 expression and suppress tumor immunity
No full textUveal melanoma (UM) is the predominant form of eye cancer. The genes GNAQ and GNA11, encoding Gq and G11 respectively, are most frequently mutated in UM and are considered the major drivers of UM carcinogenesis by activating YAP. However, the mechanisms by which metastatic UM evades the immune system remain poorly understood. In this study, we found that oncogenic mutations of Gq/G11 promoted YAP and PD-L1 expression, modifying the tumor microenvironment and promoting immune evasion of UM. Consistently, the levels of GNAQ/GNA11 and YAP positively correlated to PD-L1 expression in UM patients. Furthermore, silencing YAP or treating with its inhibitor, Verteporfin, attenuated PD-L1 expression induced by Gq/G11 mutations, thereby enhancing T cell activation and T cell-mediated cytotoxicity. Collectively, this study reveals a potential role of Gq/G11 mutations on immune evasion of UM, a new mechanism of Gq/11 mutations-induced tumorigenesis, highlighting Gq/G11 and YAP as potential immunotherapeutic targets and suggesting Verteporfin as an adjuvant for immunotherapy of UM patients with GNAQ or GNA11 mutations
Anaphylactic shock depends on endothelial Gq/G11
No full textAnaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein – coupled receptors, which are linked to the heterotrimeric G proteins Gq /G 11 , G12/G13 , and Gi . The role of downstream signaling pathways activated by anaphylactic mediators in defi ned organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of G q /G 11 - and G 12 /G 13 -mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq /G11 -mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various infl ammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial G alpha q/G alpha 11 deficiency. Mice with endothelium-specific G alpha q /G alpha 11 deficiency, but not with G alpha 12/G alpha 13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11 -mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions
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