Ectopic activity induced by elevated atrial pressure in rabbit pulmonary vein in vitro.
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Action Potentials↗
Biomedical subjects
Jie Liu
Publications and source records attributed to Jie Liu.
Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D.
UNLABELLED: Serum FGF-23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF-23 levels changed in parallel in response to changes in serum 1,25-D, suggesting that FGF-23 may be regulated by 1,25-D. In addition, the phosphaturic effect of FGF-23 may be diminished in the absence of PTH action on the kidney. INTRODUCTION: Fibroblast growth factor (FGF)-23 is a recently described hormone that has been shown to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. Three patients with mineral metabolism defects that allowed for the investigation of the regulation of FGF-23 were studied. MATERIALS AND METHODS: Patient 1 had postsurgical hypoparathyroidism and Munchausen's syndrome and consumed a pharmacologic dose of calcitriol. Patient 2 had postsurgical hypoparathyroidism and fibrous dysplasia of bone. She was treated with increasing doses of calcitriol followed by synthetic PTH(1-34). Patient 3 had pseudohypoparathyroidism type 1B and tertiary hyperparathyroidism. She underwent parathyroidectomy, which was followed by the development of hungry bone syndrome and hypocalcemia, requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all three patients. RESULTS: Patient 1 had an acute and marked increase in serum FGF-23 (70 to 670 RU/ml; normal range, 18-108 RU/ml) within 24 h in response to high-dose calcitriol administration. Patient 2 showed stepwise increases in serum FGF-23 from 117 to 824 RU/ml in response to increasing serum levels of 1alpha,25-dihydroxyvitamin D (1,25-D). Finally, before parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml; normal range, 22-67 pg/ml), and with very high serum PTH (863.7 pg/ml; normal range, 6.0-40.0 pg/ml), patient 3 had high serum FGF-23 levels (217 RU/ml). After surgery, while hypocalcemic, euphosphatemic, and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). It seemed that the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect. CONCLUSIONS: Serum FGF-23 may be regulated by serum 1,25-D, and its phosphaturic effect may be less in the absence of PTH.
Adult↗
Limited protective role of V-PYRRO/NO against cholestasis produced by alpha-naphthylisothiocyanate in mice.
O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide donor that has been shown to protect against hepatotoxic effects of endotoxin, acetaminophen and cadmium. This study examined the effects of V-PYRRO/NO on alpha-naphthylisothiocyanate (ANIT)-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (5.4mg/ml; 0.5 microl/h) starting 24h before receiving a hepatotoxic dose of ANIT (150mg/kg in olive oil, i.g.), and continuing for additional 48h (3-day pumps). V-PYRRO/NO administration partially ameliorated ANIT-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase and alkaline phosphatase, markers of liver cell death, and by improved liver pathology. However, V-PYRRO/NO had no effect on ANIT-induced cholestasis, as ANIT-increased serum bilirubin levels and gamma-glutamyl transpeptidase activity were not ameliorated. Microarray and real time RT-PCR analysis revealed that ANIT intoxication altered expression of various genes, including genes encoding metabolic enzymes, transporter proteins, acute phase proteins, inflammation- and, apoptosis-related genes, as well as other genes related to liver injury. V-PYRRO/NO treatment attenuated ANIT-induced elevations in certain inflammation- and apoptosis-related genes, but had no effect on ANIT-induced disturbance on the expression of genes related to metabolism, transport, and acute phase proteins. Thus, the liver-selective NO donor, V-PYRRO/NO, was partially protective against ANIT-induced liver injury, without affecting ANIT-induced cholestasis and cholestasis-related gene expression.
1-Naphthylisothiocyanate↗
Monitoring dopamine release from single living vesicles with nanoelectrodes.
Carbon fiber nanoelectrodes (tip diameter = ca. 100 nm) have been first used to monitor real-time dopamine release from single living vesicles of single rat pheochromocytoma (PC12) cells. The experiments show that active and inactive release sites exist on the surface of cells, and the spatial distributions have been differentiated even in the same active release zone. It is first demonstrated that multiple vesicles can sequentially release dopamine at the same site of the cell surface, which possibly plays the main role in the dopamine release from PC12 cells.
Action Potentials↗
SLOW WALKER1, essential for gametogenesis in Arabidopsis, encodes a WD40 protein involved in 18S ribosomal RNA biogenesis.
The progression of mitotic division cycles and synchronous development between and within the male and female reproductive organs are essential for plant sexual reproduction. Little is known about the genetic control of the progression of mitotic cycles of the haploid genome during gametogenesis in higher plants. Here, we report the phenotypic and molecular characterization of an Arabidopsis thaliana mutant, slow walker1 (swa1), in which the progression of the mitotic division cycles of the female gametophyte was disrupted. Confocal microscopy revealed that megagametophyte development was asynchronous in swa1, causing embryo sacs to arrest at two-, four-, or eight-nucleate stages within the same pistil. A delayed pollination experiment showed that a small fraction of the swa1 embryo sacs were able to develop into functional female gametophytes. The swa1 mutation also showed a slight reduction in penetrance through the male gametophyte, although the pollen grains were morphologically normal. Molecular analysis indicates that SWA1 encodes a protein with six WD40 repeats that is localized in the nucleolus in interphase cells. The SWA1 gene is expressed in cells undergoing active cell divisions, including functional megaspores and the female gametophytic cells. RNA interference results indicated that knockout of SWA1 inhibited root growth significantly and led to the accumulation of unprocessed 18S pre-rRNA. These data suggest that SWA1 most likely plays a role in rRNA biogenesis that is essential for the progression of the mitotic division cycles during gametogenesis in plants.
Amino Acid Sequence↗
Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a.
We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the Scn5a gene to clarify the role of Scn5a-encoded cardiac Na+ channels in normal SAN function and the mechanism(s) by which reduced Na+ channel function might cause sinus node dysfunction. Scn5a+/- mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na+ channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a+/- SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a+/- SAN preparations. Furthermore, isolated WT and Scn5a+/- SAN cells demonstrated differing correlations between cycle length, maximum upstroke velocity and action potential amplitude, and cell size. Small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SAN cells in the reduced pacemaker rate that was observed in Scn5a+/- myocytes. These findings were successfully reproduced in a model that implicated i(Na) directly in action potential propagation through the SAN and from SAN to atria, and in modifying heart rate through a coupling of SAN and atrial cells. Functional alterations in the SAN following heterozygous-targeted disruption of Scn5a thus closely resemble those observed in clinical sinus node dysfunction. The findings accordingly provide a basis for understanding of the role of cardiac-type Na+ channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.
Action Potentials↗
Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans.
The pathways for differentiation of human CD4(+) T cells into functionally distinct subsets of memory cells in vivo are unknown. The identification of these subsets and pathways has clear implications for the design of vaccines and immune-targeted therapies. Here, we show that populations of apparently naive CD4(+) T cells express the chemokine receptors CXCR3 or CCR4 and demonstrate patterns of gene expression and functional responses characteristic of memory cells. The proliferation history and T cell receptor repertoire of these chemokine-receptor(+) cells suggest that they are very early memory CD4(+) T cells that have "rested down" before acquiring the phenotypes described for "central" or "effector" memory T cells. In addition, the chemokine-receptor(+) "naive" populations contain Th1 and Th2 cells, respectively, demonstrating that Th1/Th2 differentiation can occur very early in vivo in the absence of markers conventionally associated with memory cells. We localized ligands for CXCR3 and CCR4 to separate foci in T cell zones of tonsil, suggesting that the chemokine-receptor(+) subsets may be recruited and contribute to segregated, polarized microenvironments within lymphoid organs. Importantly, our data suggest that CD4(+) T cells do not differentiate according to a simple schema from naive --> CD45RO(+) noneffector/central memory --> effector/effector memory cells. Rather, developmental pathways branch early on to yield effector/memory populations that are highly heterogeneous and multifunctional and have the potential to become stable resting cells.
CD4-Positive T-Lymphocytes↗
Role of Ras/PKCzeta/MEK/ERK1/2 signaling pathway in angiotensin II-induced vascular smooth muscle cell proliferation.
The role of protein kinase C (PKC) and its cross talk with extracellular signal-regulated kinase (ERK) cascade in angiotensin II (AngII)-elicited vascular smooth muscle cell (VSMC) proliferation are still unclear. In this study, the PKC pathway of AngII to activate ERK1/2 and induce cell proliferation was investigated in rat aortic smooth muscle cells. The proliferation of VSMCs was tested by [3H]-thymidine incorporation assay. Phosphorylated and non-phosphorylated PKCzeta, ERK1/2, Elk-1, and mitogen-activated ERK-activating kinase (MEK) were estimated by Western blot analysis. The interactions of signal molecules were examined by immunoprecipitation. AngII-induced VSMC proliferation and activation of ERK1/2 and nuclear transcription factor Elk-1 were all down-regulated by PKC non-specific inhibitor (staurosporine) and PKCzeta pseudosubstrate inhibitor (PS-PKCzeta). Dominant negative Ras transfection into VSMCs decreased AngII-induced PKCzeta and ERK1/2 phosphorylation. AngII stimulated the association of PKCzeta with Ras. AngII-induced MEK phosphorylation was inhibited by PKCzeta pseudosubstrate inhibitor and the PKCzeta-MEK complex was detected by immunoprecipitation. These results suggest that PKCzeta isoform is involved in VSMC proliferation and Elk-1 activation. AngII can activate ERK1/2 by Ras/PKCzeta/MEK pathway, which may be one of the important signal transduction pathways in AngII-induced VSMC proliferation.
Angiotensin II↗
Alternative Gnas gene products have opposite effects on glucose and lipid metabolism.
Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein alpha-subunit (G(s)alpha), the G protein required for receptor-stimulated cAMP production; extralarge G(s)alpha (XLalphas), a paternally expressed G(s)alpha isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G(s)alpha undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2m-/+) or paternal (E2+/p-) allele results in opposite effects on energy metabolism. E2m-/+ mice are obese and hypometabolic, whereas E2+/p- mice are lean and hypermetabolic. We now studied the effects of G(s)alpha deficiency without disrupting other Gnas gene products by deleting G(s)alpha exon 1 (E1). E1+/p- mice lacked the E2+/p- phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2+/p- phenotype appears to result from XLalphas deficiency, whereas loss of paternal-specific G(s)alpha expression in E1+/p- mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2m-/+ mice, E1m-/+ mice had s.c. edema at birth, presumably due to loss of maternal G(s)alpha expression. However, E1m-/+ mice differed from E2m-/+ mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1m-/+ mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1+/p- mice. Differences between E1m-/+ and E1+/p- mice presumably result from differential effects on G(s)alpha expression in tissues where G(s)alpha is normally imprinted.
Alternative Splicing↗
Improved procedure on the microscopic approach to determine colloidal stability.
We present an improved procedure on the approach to determine the stability of polystyrene spheres at microscopic particle levels by means of artificially induced particle collisions with the aid of optical tweezers [J. Chem. Phys. 119, 2399 (2003)]. The basic consideration on this new development is that the major contribution to the sticking probability for a particle pair caught into the optical trap for a short period is from its single collision; therefore, if the trapping duration for the pair is taken to be short, the accumulated sticking probability will be a good approximation for the single collision. The experimental procedure associated with this approximation does not resort to exactly controlling the short trapping duration or request the trapping duration correction as previously reported, and therefore it is more practical and applicable for a broader range of the stability ratio. The experimental results under different electrolyte concentrations by the new procedure are consistent with those from the turbidity measurements.
Journal Article↗
Hepatitis B virus X antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis.
Hepatitis B and related viruses that infect mammalian hosts encode the "X" protein that has been shown to contribute importantly to the pathogenesis of chronic liver disease (CLD) and to the development of hepatocellular carcinoma (HCC). In a variety of tissue culture systems, hepatitis B virus (HBV) X antigen, or HBxAg, has been shown to trigger apoptosis, while other evidence suggests that HBxAg inhibits apoptosis and stimulates the cell cycle by constitutively activating a number of signaling pathways that are important for hepatocellular growth and survival. These apparently contrasting properties of HBxAg may be associated with differences in the X protein itself, since carboxy-terminal truncated forms of HBxAg appear to be associated with HCC lesions. Alternatively, or in addition, these differences may be due to the cell type, state of cell differentiation, and whether expression occurs in resting or dividing cells. Further, the association between HBxAg expression and chromosomal instability, may also contribute to the apparently contrasting fates of HBxAg positive cells. It is proposed that in many of these systems, the different outcomes of HBxAg expression may be due to the nature of the cellular response to HBxAg, and not due to differences in the fundamental properties of HBxAg, the latter of which promote cell survival, cell cycle progression, and the development of HCC.
Animals↗
Electronic effect of different positions of the -NO2 group on the DNA-intercalator of chiral complexes [Ru(bpy)2L]2+ (L =o-npip, m-npip and p-npip).
New chiral Ru(II) complexes with intercalators L (L =o-npip, m-npip and p-npip) containing -NO2 at different positions on the phenyl ring were synthesized and characterized by elemental analysis, 1H NMR, ESI-MS and CD spectra. The DNA binding properties of these complexes have been investigated with UV-Vis, emission spectra, CD spectra and viscosity measurements. A subtle but detectable difference was observed in the interaction of these isomers with CT-DNA. Absorption spectroscopy experiments indicated that each of these complexes can interact with the DNA. The DNA-binding of the Delta-isomer is stronger than that of Lambda-isomer. DNA-viscosity experiments provided evidence that both Delta- and Lambda-[Ru(bpy)2(o-npip)](PF6)2 bind to DNA with partial intercalation, and both Delta- and Lambda-[Ru(bpy)(2)(p-npip)](PF6)2 fully intercalate with DNA. However, Delta- and Lambda- [Ru(bpy)2(m-npip)](PF6)2 bind to DNA through different modes, i.e., the Delta isomer by intercalation and Lambda isomer by partial intercalation. Under irradiation with UV light, Ru(II) complexes showed different efficiency of cleaving DNA. The most interesting feature is that neither 1 (Delta-1 and Lambda-1) nor 3 (Delta-3 and Lambda-3) emit luminescence either alone in aqueous solution or in the presence of DNA, whereas both Delta-2 and Lambda-2 emit luminescence under the same conditions. In addition, theoretical calculations for these three isomer complexes have been carried out applying the density functional theory (DFT) method at the level of the B3LYP/LanL2DZ basis set, and the calculated results can reasonably explain the obtained experimental trends in the DNA-binding affinities or binding constants (Kb) and some spectral properties of the complexes.
2,2'-Dipyridyl↗
Etching of carbon nanotubes by ozone--a surface area study.
The oxidative etching of single walled carbon nanotubes (SWNTs) is useful for opening the end caps and the sidewalls of the nanotubes to provide access to the interior. We have studied the effect of successive treatment of SWNTs by 95% pure O(3)(g), which is a powerful and convenient oxidizing agent. The surface area of the SWNTs was measured following exposure to O(3)(g) at 300 K and also following heating to 1073 K in a vacuum to decompose the oxidized groups on the nanotubes, a procedure called etching. This O(3)-induced etching process was observed by scanning electron microscopy and by transmission electron microscopy, and the kinetics of the process was studied gravimetrically. It was found that O(3) attack occurs preferentially on the outermost geometric surface of the conglomerate sample of the nanotubes as a result of the high efficiency of O(3) to react in a few collisions with the nanotube surface. Ozone-induced etching causes the loss of pores in the 20 A diameter range as observed by nitrogen adsorption at equilibrium by density functional theory analysis.
Journal Article↗
Growth-promoting effect of platelet-derived growth factor on rat cardiac myocytes.
Platelet-derived growth factor (PDGF) is a dimeric molecule consisting of disulfide-bonded A- and B-polypeptide chains. Homodimeric (PDGF-AA, PDGF-BB) as well as heterodimeric (PDGF-AB) isoforms exert their effects on target cells by binding with different specificities to two structurally related protein tyrosine kinase receptors, denoted alpha- and beta-receptors. PDGF stimulates growth in various cell types, but little is known about its effect on mammalian cardiomyocytes. Therefore, growth-promoting effect of PDGF on rat cardiomyocytes was investigated. Primary culture of neonatal rat ventricular myocytes was prepared and cellular growth was estimated by [3H]-leucine incorporation assay. Tyrosine-phosphorylated PDGF-beta receptor of cardiomyocytes was determined by immunoblotting analysis after immunoprecipitation. PDGF-beta receptor, extracellular signal-regulated kinase (ERK) 1/2 and phosphorylated ERK1/2 of cardiomyocytes were measured by immunoblotting analysis. [3H]-leucine incorporation into the cultured myocytes was increased in a time- and dose-dependent manner after PDGF-BB stimulation. Phosphorylation of PDGF-beta receptor and ERK1/2 in cardiomyocytes was increased after short-term stimulation of PDGF-BB. Protein expression of PDGF-beta receptor and ERK1/2 was increased after long-term stimulation of PDGF-BB. [(3)H]-leucine incorporation into the cultured myocytes induced by PDGF-BB was partly blocked by mitogen-activated ERK-activating kinase (MEK) inhibitor PD98059, phospholipase C (PLC) inhibitor U73122, and protein kinase C (PKC) inhibitor staurosporin aglycone, respectively. Therefore, PDGF beta receptor, ERK1/2, PLC and PKC are involved in the signal transduction of PDGF-induced growth response of rat cardiac myocytes.
Animals↗
Geometric phase for adiabatic evolutions of general quantum states.
The concept of a geometric phase (Berry's phase) is generalized to the case of noneigenstates, which is applicable to both linear and nonlinear quantum systems. This is particularly important to nonlinear quantum systems, where, due to the lack of the superposition principle, the adiabatic evolution of a general state cannot be described in terms of eigenstates. For linear quantum systems, our new geometric phase reduces to a statistical average of Berry's phases. Our results are demonstrated with a nonlinear two-level model.
Journal Article↗
Cadmium-induced malignant transformation in rat liver cells: role of aberrant oncogene expression and minimal role of oxidative stress.
Our study examined the role of oxidative stress and aberrant gene expression in malignant transformation induced by chronic, low-level cadmium exposure in non-tumorigenic rat liver epithelial cell line, TRL 1215. Cells were cultured in 1.0 microM cadmium (as CdCl(2)) for up to 28 weeks and compared to passage-matched control cells. The level of cadmium used for transformation produced no evidence of increased superoxide (O(2) (-*.)) or hydrogen peroxide (H(2)O(2)) levels in the early stages of exposure (</=24 hr). The chronic cadmium exposed liver epithelial cells (CCE-LE) were hyperproliferative with a growth rate about 3-fold higher than control cells. CCE-LE cells produced highly aggressive tumors upon inoculation into mice confirming malignant transformation. Analysis of cellular reactive oxygen species (ROS) showed that CCE-LE cells possessed markedly lower basal levels of intracellular O(2) (-*.)and H(2)O(2) and were very tolerant to high-dose (50 microM) cadmium-induced ROS. Time course studies showed the production of ROS by high-dose cadmium was abolished well in advance of malignant transformation. In contrast, marked overexpression of the oncogenes c-myc and c-jun occurred in transformed CCE-LE cells as evidenced by up to 10-fold increases in both transcript and protein. A significant increase in DNA-binding activity of the transcription factors AP-1 and NF-kappaB occurred in CCE-LE cells. Increases in oncogene expression and transcription factor activity occurred concurrently with malignant transformation. Thus, cadmium-induced ROS occurs as an early, high-dose event but is abolished well in advance of malignant transformation. Low-level chronic cadmium triggers oncogene overexpression possibly by altering critical transcription factor activity. Such changes in cellular gene expression likely culminate in the loss of growth control and cadmium-induced neoplastic transformation in CCE-LE cells, whereas generation of ROS by cadmium seemed to play a minimal role in this transformation.
Animals↗
Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase.
The endocannabinoid anandamide exerts neurobehavioral, cardiovascular, and immune-regulatory effects through cannabinoid receptors (CB). Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the in vivo degradation of anandamide. Recent experimental studies have suggested that targeting the endocannabinergic system by FAAH inhibitors is a promising novel approach for the treatment of anxiety, inflammation, and hypertension. In this study, we compared the cardiac performance of FAAH knockout (FAAH-/-) mice and their wild-type (FAAH+/+) littermates and analyzed the hemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters, systolic and diastolic function at different preloads, and baroreflex sensitivity were similar in FAAH-/- and FAAH+/+ mice. FAAH-/- mice displayed increased sensitivity to anandamide-induced, CB1-mediated hypotension and decreased cardiac contractility compared with FAAH(+/+) littermates. In contrast, the hypotensive potency of synthetic CB1 agonist HU-210 and the level of expression of myocardial CB1 were similar in the two strains. The myocardial levels of anandamide and oleoylethanolamide, but not 2-arachidonylglycerol, were increased in FAAH-/- mice compared with FAAH+/+ mice. These results indicate that mice lacking FAAH have a normal hemodynamic profile, and their increased responsiveness to anandamide-induced hypotension and cardiodepression is due to the decreased degradation of anandamide rather than an increase in target organ sensitivity to CB1 agonists.
Amidohydrolases↗
Identification of the control region for tissue-specific imprinting of the stimulatory G protein alpha-subunit.
Gnas is a complex gene with multiple imprinted promoters. The upstream Nesp and Nespas/Gnasxl promoters are paternally and maternally methylated, respectively. The downstream promoter for the stimulatory G protein alpha-subunit (G(s)alpha) is unmethylated, although in some tissues (e.g., renal proximal tubules), G(s)alpha is poorly expressed from the paternal allele. Just upstream of the G(s)alpha promoter is a primary imprint mark (1A region) where maternal-specific methylation is established during oogenesis. Pseudohypoparathyroidism type 1B, a disorder of renal parathyroid hormone resistance, is associated with loss of 1A methylation. Analysis of embryos of Dnmt3L(-/-) mothers (which cannot methylate maternal imprint marks) showed that Nesp, Nespas/Gnasxl, and 1A imprinting depend on one or more maternal primary imprint marks. We generated mice with deletion of the 1A differentially methylated region. These mice had normal Nesp-Nespas/Gnasxl imprinting, indicating that the Gnas locus contains two independent imprinting domains (Nespas-Nespas/Gnasxl and 1A-G(s)alpha) controlled by distinct maternal primary imprint marks. Paternal, but not maternal, 1A deletion resulted in G(s)alpha overexpression in proximal tubules and evidence for increased parathyroid hormone sensitivity but had no effect on G(s)alpha expression in other tissues where G(s)alpha is normally not imprinted. The 1A region is a maternal imprint mark that contains one or more methylation-sensitive cis-acting elements that suppress G(s)alpha expression from the paternal allele in a tissue-specific manner.
Animals↗