Rhes and AGS1/Dexras1 affect signaling by dopamine D1 receptors through adenylyl cyclase

Abstract

The GTP binding proteins Rhes and AGS1/Dexras1 define a subfamily of the Ras superfamily and have been shown to affect signaling by G protein-coupled receptors. We tested the effects of both proteins at an early stage of signaling by dopamine receptors-activation of adenylyl cyclase. Rhes decreased dopamine D1 receptor agonist-stimulated cAMP accumulation in a pertussis toxin-sensitive manner. It had no effect on cAMP accumulation in the absence of agonist. AGS1/ Dexras1, on the other hand, decreased cAMP accumulation in both vehicle-treated and agonisttreated cells, resulting in a higher percent stimulation by agonist, or a higher signal-to-noise ratio. The effects of AGS1/Dexras1 on cAMP accumulation were not blocked by pertussis toxin, suggesting that it may produce these effects through interaction with a G α i monomer. Both Rhes and AGS1/Dexras1 associated with GTP-bound G α i in pull-down assays. However, Rhes had no effect on the ability of activated D2 receptor to inhibit cAMP. Neither Rhes nor AGS1/Dexras1 interacted with the D1 receptor in pull-down assays. These findings show that in addition to its well-known effects on signaling through Gi-coupled receptors, AGS1/Dexras1 can affect signaling through a Gs/olf-coupled receptor. Furthermore, they suggest that Rhes exerts some of its effects by interacting with G α i.

<i>Rasd1</i> is an estrogen-responsive immediate early gene and modulates expression of late genes in rat anterior pituitary cells

“…In addition to the changes of basal mRNA expression of Pim3, Igf1 and Giot1 genes by Rasd1 knockdown, we found notable changes in E2 late induction of Pim3 and Fosl1 genes that encode a protooncogene with serine/ threonine kinase activity [34] and a component of the AP-1 transcription factor complex [35], respectively; E2 stimulation of Pim3 expression was enhanced and inhibition of Fosl1 expression was eliminated. These In the present study we demonstrated that knockdown of Rasd1 mRNA expression markedly increased CRE-containing promoter activity, consistent with the finding that Rasd1 inhibits adenylyl cyclase leading to inhibition of CREB activation [11,27,28]. However, whether a change in CRE-containing promoter activity or a combination of changes in CRE, AP-1 and SRE promoter activities shown to be accompanied by Rasd1 knockdown is responsible for the changes in mRNA expression of the estrogen-responsive late genes such as Pim3 and Fosl1 genes is unclear.…”

“…We showed that mRNA expression levels of Rasd1 in pituitary cells were not altered by the potent mitogen IGF-1, but were suppressed by serum supplementation and treatment with forskolin, which increases cAMP levels. The inhibitory effect of forskolin is noteworthy because others demonstrated that Rasd1 expression suppressed the adenylyl cyclase/cAMP/protein kinase A/CREB pathway [11, 27,28]. Taken together, these findings suggest the existence of a regulatory loop in which stimulation of adenylyl cyclase/cAMP enhances its own activity and production by inhibiting Rasd1 expression.…”

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…Group I AGS proteins, which include AGS1 (Dexras1, RASD1); resistance to inhibitors of cholinesterase (Ric)-8A and -8B; Ga-interacting, vesicleassociated protein (GIV)/Girdin/Akt-phosphorylation enhancer, act as nonreceptor guanine nucleotide exchange factors (GEFs) for Ga and/or Gabg (Cismowski et al, , 2000Tall et al, 2003;Tall and Gilman, 2005;Garcia-Marcos et al, 2009;Chan et al, 2011aChan et al, , 2013Tall, 2013). Ras homolog enriched in striatum (Rhes) or RASD2, which exhibits 66% amino acid similarity to AGS1, interacts with Gai, and regulates G protein signaling, may be included in this group of AGS proteins, although it has not yet been shown to exhibit GEF activity in experiments with purified proteins (Falk et al, 1999;Vargiu et al, 2004;Thapliyal et al, 2008;Harrison and He, 2011). The Saccharomyces cerevisiae protein Arr4 also acts as a GEF for the yeast G protein GPA1 (Lee and Dohlman, 2008).…”

“…The group I AGS proteins exhibit selectivity in their interaction with G proteins: AGS1 (Gai, Gao, Gai/obg) (Cismowski et al, , 2000; Ric-8A (Gai, Gao, Gq, Ga13) (Tall et al, 2003;Tall and Gilman, 2005;Thomas et al, 2008;Chan et al, 2011aChan et al, , 2013Gabay et al, 2011); Ric-8B (Gas, Gaolf) (Chan et al, 2011a,b); GIV/Girdin (Gai, Gas) (Le-Niculescu et al, 2005;Garcia-Marcos et al, 2009Ghosh et al, 2010;Beas et al, 2012); and Rhes (Gai) (Harrison and He, 2011). The group I proteins have broad functional impact influencing tissue development, cell growth, and/or neuronal signaling (Fig.…”

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

“…43 Also Rasd1 has a function to regulate neurotransmitter mediated behaviors 44 and cancers. 45 The functional relationship between TRPC4 and small GTPase Rasd1…”