The Cloning and Expression of a New Guanylyl Cyclase Orphan Receptor

Schulz, Stephanie; Wedel, Barbara J.; Matthews, Anne; Garbers, David L.

doi:10.1074/jbc.273.2.1032

Cited by 89 publications

(62 citation statements)

References 36 publications

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“…In addition, CNP seems to be a local regulator of ACTH-induced aldosterone secretion in bovine adrenal zona glomerulosa cells (20). We also detected the presence of transcripts for mGC-G, which is an orphan receptor (39). So far, mGC-G has been identified in the rat lung, small intestine, skeletal muscles, and kidney (27), as well as in mouse testicular tissue, but without the precise location within the testis (24).…”

Section: Discussionmentioning

confidence: 76%

Protein kinase G-mediated stimulation of basal Leydig cell steroidogenesis

Andrić

Janjic²,

Stojkov³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

113

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The androgen-secreting Leydig cells produce cGMP, but the pathways responsible for generation and actions of this intracellular messenger have been incompletely characterized in these cells. Here, we show the presence of mRNA transcripts for the membrane-bound and soluble guanylyl cyclases (sGC), the cGMP-specific phosphodiesterase 5, and the cGMP-dependent protein kinase I (PKG I) and PKG II in purified rat Leydig cells from adult animals. Stimulation of both guanylyl cyclases and inhibition of phosphodiesterase 5 in vitro were accompanied by elevations in cGMP and androgen production, whereas inhibition of sGC and PKG led to a decrease in steroidogenesis. The stimulatory action of cGMP on steroidogenesis was preserved in cells with inhibited cAMP-dependent protein kinases. Experiments with exogenously added substrates revealed the dependence of cGMP-induced progesterone and androgen synthesis on cholesterol but not on 22-OH cholesterol, pregnenolone, progesterone, and Δ4-androstenedione. Treatment with nitric oxide donor increased phosphorylation of the steroidogenic acute regulatory protein (StAR). In contrast, inhibition of sGC and PKG, but not protein kinase A, significantly reduced StAR phosphorylation. These results suggest that cGMP contributes to the control of basal steroidogenesis in Leydig cells through the PKG-dependent modification of the StAR protein.

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Section: Discussionmentioning

confidence: 76%

Protein kinase G-mediated stimulation of basal Leydig cell steroidogenesis

Andrić

Janjic²,

Stojkov³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

113

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“…11,28 Although the full-length cDNA for mouse GC-G (Gucy2g) was originally isolated from the testis, GC-G mRNA was also found in the kidney by a more sensitive RT-PCR method (Figure 1), as compared with findings from Northern blot analysis. 11 This finding is further supported by immunohistochemistry, validating GC-G protein expression in renal tubular epithelial cells (Figure 2, E and G, and Supplemental Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

Lin

Cheng²,

Hou

et al. 2008

Journal of the American Society of Nephrology

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The membrane forms of guanylyl cyclase (GC) serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. Rat kidney contains mRNA for the GC-G isoform, but the role of this receptor in health and disease has not been characterized. It was found that mouse kidney also contains GC-G mRNA, and immunohistochemistry identified GC-G protein in the epithelial cells of the proximal tubule and collecting ducts. Six hours after ischemia-reperfusion (I/R) injury, GC-G mRNA and protein expression increased three-fold and remained upregulated at 24 h. For determination of whether GC-G mediates I/R injury, a mutant mouse with a targeted disruption of the GC-G gene (Gucy2g) was created. At baseline, no histologic abnormalities were observed in GC-G Ϫ/Ϫ mice. After I/R injury, elevations in serum creatinine and urea were attenuated in GC-G Ϫ/Ϫ mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation. Measures of inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin) and activation of NF-B were lower in GC-G Ϫ/Ϫ mice compared with wild-type mice. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G Ϫ/Ϫ mice resulted in a dramatically higher mortality after renal I/R injury, further supporting a role for GC-G in mediating injury. In summary, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury.

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“…Specific activators of soluble or particulate GC were studied in the next set of experiments. Among the seven membrane GC (GC-A to -G) (43,44), ligands have been characterized for three. They are ANP and brain natriuretic peptide (BNP) for GC-A; CNP for GC-B; and heat-stable enterotoxin (STa), guanylin, and uroguan for GC-C (43).…”

Section: Induction Of No Release Inos Protein and Mrna Expression Dmentioning

confidence: 99%

Cyclic GMP and cGMP-binding Phosphodiesterase Are Required for Interleukin-1-induced Nitric Oxide Synthesis in Human Articular Chondrocytes

Geng¹,

Zhou²,

Thompson³

et al. 1998

Journal of Biological Chemistry

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This study addressed the role of guanylyl cyclase (GC) and phosphodiesterase (PDE) in interleukin (IL)-1 activation of human articular chondrocytes. The GC inhibitors LY83583 and methylene blue dose-dependently inhibited IL-1-induced nitric oxide (NO) production, inducible NO synthase (iNOS) protein, and mRNA expression. These effects of GC inhibition were consistent with the rapid induction of cGMP by IL-1, which reached maximal levels after 5 min. The effects of GC inhibitors were selective as they did not reduce IL-1-induced cyclooxygenase II protein and mRNA. An inhibitor specific for soluble GC did not affect IL-1-induced NO production, and activators of soluble GC did not induce NO. However, the expression of iNOS mRNA was induced by atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), activators of particulate GC, indicating that particulate rather than soluble guanylyl cyclases were involved in iNOS induction. The expression of iNOS mRNA and the production of NO were induced by a slowly hydrolyzable analog of cGMP, 8-bromo-cGMP, but not by nonhydrolyzable analog, dibutyryl cGMP, suggesting that PDE rather than cGMP-dependent protein kinase mediates the cGMP effects. Chondrocytes contained extensive cGMP PDE activity. This had PDE5 biochemical features and an inhibitor profile consistent with PDE5. Furthermore, the nonisoformspecific PDE inhibitor IBMX and PDE5-specific inhibitors suppressed IL-1-induced NO release and iNOS mRNA expression. PDE5 mRNA was constitutively expressed in chondrocytes. In addition to increasing PDE5 activities, IL-1 treatment reduced the sensitivity of PDE5 to several pharmacological inhibitors by up to 50-fold. In summary, inhibitors of either GC or PDE5 prevented IL-1 induction of iNOS; IL-1 increased the rates of both cGMP generation and hydrolysis; and exogenous PDE hydrolyzable cGMP analog induced iNOS and NO. These results suggest that increased cGMP metabolic flux is sufficient to induce iNOS, and GC and PDE5 activities are required for IL-1 induction of iNOS expression via increases in coupled cGMP synthesis and hydrolysis. IL-11 promotes cartilage catabolism through the induction of proteases and the inhibition of extracellular matrix synthesis. IL-1 inhibits chondrocyte proliferation and suppresses collagen type II and aggrecan production (1). Some of these effects are mediated by the IL-1 induction of nitric oxide (2, 3). IL-1-induced signal transduction occurs via two IL-1 receptor subunits, the IL-1 receptor I (IL-1RI) and the IL-1 receptor accessory protein (IL-1RAcP) (4, 5). Diverse intracellular signaling pathways are activated by IL-1. Although there are tissuespecific differences in the IL-1-activated signaling pathways, even in the same cell type there are multiple IL-1-induced second messengers that differentially regulate subsets of IL-1-responsive genes. In smooth muscle cells, IL-1 can activate guanylyl cyclase in nitric oxide (NO)-dependent and NO-independent pathways (6, 7). IL-1 activates phospholipase A 2 (8) and stimulates expression...

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The Cloning and Expression of a New Guanylyl Cyclase Orphan Receptor

Cited by 89 publications

References 36 publications

Protein kinase G-mediated stimulation of basal Leydig cell steroidogenesis

Protein kinase G-mediated stimulation of basal Leydig cell steroidogenesis

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

Cyclic GMP and cGMP-binding Phosphodiesterase Are Required for Interleukin-1-induced Nitric Oxide Synthesis in Human Articular Chondrocytes

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