Publications
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Jonas KC, Hanyaloglu AC, 2017, Impact of G protein-coupled receptor heteromers in endocrine systems, Molecular and Cellular Endocrinology, Vol: 449, Pages: 21-27, ISSN: 0303-7207
The fine-tuning of endocrine homeostasis is regulated by dynamic receptor mediated processes. Thesuperfamily of G protein-coupled receptors (GPCRs) have diverse roles in the modulation of all endocrineaxes, thus understanding the mechanisms underpinning their functionality is paramount for treatmentof endocrinopathies. Evidence over the last 20 years has highlighted homo and heteromerization as a keymode of mediating GPCR functional diversity. This review will discuss the concept of GPCR heteromerizationand its relevance to endocrine function, detailing in vitro and in vivo evidence, and exploringcurrent and potential pharmacological strategies for specific targeting of GPCR heteromers in endocrineheath and disease.
Jonas KC, Huhtaniemi I, Hanyaloglu AC, 2016, Single-molecule resolution of G protein-coupled receptor (GPCR) complexes, G PROTEIN-COUPLED RECEPTORS: SIGNALING, TRAFFICKING AND REGULATION, Editors: Shukla, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 55-72, ISBN: 978-0-12-803595-5
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- Citations: 29
Jonas KC, Fanelli F, Huhtaniemi IT, et al., 2015, Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies, Journal of Biological Chemistry, Vol: 290, Pages: 3875-3892, ISSN: 1083-351X
Background: GPCRs form complex oligomers whose role in signaling is poorly understood.Results: Super-resolution imaging of functionally asymmetric oligomers reveals diverse functional and structural organizationsand the ability to alter signal responses.Conclusion: GPCR oligomers may fine-tune receptor signaling by altering the functional role of individual protomers.Significance: Distinct oligomers could be exploited pharmacologically to improve efficacy, selectivity, and/or specificity.
Jonas KC, Oduwole OO, Peltoketo H, et al., 2014, Mouse models of altered gonadotrophin action: insight into male reproductive disorders, REPRODUCTION, Vol: 148, Pages: R63-R70, ISSN: 1470-1626
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- Citations: 19
Jonas KC, Fanelli F, Huhtaniemi IT, et al., 2014, Single Molecule Analysis of GPCR Transactivation Via PD-PALM Reveals Oligomeric Complexes That Regulate Signal Sensitivity, ENDOCRINE REVIEWS, Vol: 35, ISSN: 0163-769X
Rivero-Muller A, Jonas KC, Hanyaloglu AC, et al., 2013, Di/Oligomerization of GPCRs-Mechanisms and Functional Significance, OLIGOMERIZATION IN HEALTH AND DISEASE, Vol: 117, Pages: 163-185, ISSN: 1877-1173
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- Citations: 34
Jonas KC, Rivero-Mueller A, Huhtaniemi IT, et al., 2013, G Protein-Coupled Receptor Transactivation: From Molecules to Mice, RECEPTOR-RECEPTOR INTERACTIONS, Vol: 117, Pages: 433-450, ISSN: 0091-679X
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- Citations: 14
Nagirnaja L, Venclovas C, Rull K, et al., 2012, STRUCTURAL AND FUNCTIONAL ANALYSIS OF RARE MISSENSE MUTATIONS IN HUMAN CHORIONIC GONADOTROPIN β-SUBUNIT, Meeting of the International-Federation-of-Placenta-Associations (IFPA), Publisher: W B SAUNDERS CO LTD, Pages: A61-A61, ISSN: 0143-4004
Nagirnaja L, Venclovas C, Rull K, et al., 2012, Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β-subunit, MOLECULAR HUMAN REPRODUCTION, Vol: 18, Pages: 379-390
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- Citations: 14
Rivero-Müller A, Chou YY, Ji I, et al., 2010, Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation, Proc Natl Acad Sci U S A., Vol: 5, Pages: 2319-2324
Thompson IR, Chand AN, Jonas KC, et al., 2009, Molecular characterisation and functional interrogation of a local natriuretic peptide system in rodent pituitaries, alphaT3-1 and LbetaT2 gonadotroph cells., J Endocrinol, Vol: 203, Pages: 215-229
In the pituitary, C-type natriuretic peptide (CNP) has been implicated as a gonadotroph-specific factor, yet expression of the CNP gene (Nppc) and CNP activity in gonadotrophs is poorly defined. Here, we examine the molecular expression and putative function of a local gonadotroph natriuretic peptide system. Nppc, along with all three natriuretic peptide receptors (Npr1, Npr2 and Npr3), was expressed in both alphaT3-1 and LbetaT2 cells and primary mouse pituitary tissue, yet the genes for atrial-(ANP) and B-type natriuretic peptides (Nppa and Nppb) were much less abundant. Putative processing enzymes of CNP were also expressed in alphaT3-1 cells and primary mouse pituitaries. Transcriptional analyses revealed that the proximal 50 bp of the murine Nppc promoter were sufficient for GNRH responsiveness, in an apparent protein kinase C and calcium-dependent manner. Electrophoretic mobility shift assays showed Sp1/Sp3 proteins form major complexes within this region of the Nppc promoter. CNP protein was detectable in rat anterior pituitaries, and electron microscopy detected CNP immunoreactivity in secretory granules of gonadotroph cells. Pharmacological analyses of natriuretic peptide receptor activity clearly showed ANP and CNP are potent activators of cGMP production. However, functional studies failed to reveal a role for CNP in regulating cell proliferation or LH secretion. Surprisingly, CNP potently stimulated the human glycoprotein hormone alpha-subunit promoter in LbetaT2 cells but not in alphaT3-1 cells. Collectively, these findings support a role for CNP as the major natriuretic peptide of the anterior pituitary, and for gonadotroph cells as the major source of CNP expression and site of action.
Jonas KC, Chandras C, Abayasekara DRE, et al., 2006, Role for prostaglandins in the regulation of type 1 11beta-hydroxysteroid dehydrogenase in human granulosa-lutein cells., Endocrinology, Vol: 147, Pages: 5865-5872, ISSN: 0013-7227
11beta-hydroxysteroid dehydrogenase (11betaHSD) enzymes regulate glucocorticoid availability in target tissues. 11betaHSD1 is the predominant isoenzyme expressed and active in human granulosa-lutein (hGL) cells. This study investigated the effects of pharmacological inhibitors of prostaglandin (PG) synthesis on 11betaHSD1 activities and expression in hGL cells. The consequences for 11betaHSD1 of increasing exposure of hGL cells to PGs, either by treatment with exogenous PGs or by challenging cells with IL-1beta, were also assessed. Suppression of basal PG synthesis using four different inhibitors of PG H synthase enzymes [indomethacin, niflumic acid, meclofenamic acid (MA) and N-(2-cyclohexyloxy-4-nitorophenyl) methane sulfonamide (NS-398)] each resulted in significant decreases in both cortisol oxidation and cortisone reduction. Both activities of 11betaHSD1 were suppressed by up to 64+/-6% (P<0.05). Over 4 and 24 h, neither MA nor NS-398 affected the expression of 11betaHSD1 protein, suggesting enzyme regulation by PGs at the posttranslational level. When cells were cotreated for 4 h with PGHS inhibitors plus 30 nm PGD2, PGF2alpha, or PGE2, each PG overcame the suppression of cortisol oxidation by indomethacin or MA. Treatment of hGL cells with IL-1beta increased the concentrations of both PGE2 and PGF2alpha, accompanied by a 70+/-25% increase in net cortisol oxidation. All three responses to IL-1beta were abolished when cells were cotreated with MA. These findings suggest a role for PGs in the posttranslational regulation of 11betaHSD1 activities in hGL cells.
Thurston LM, Norgate DP, Jonas KC, et al., 2003, Ovarian modulators of type 1 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity and intra-follicular cortisol:cortisone ratios correlate with the clinical outcome of IVF., Hum Reprod, Vol: 18, Pages: 1603-1612, ISSN: 0268-1161
BACKGROUND: Follicular fluid (FF) contains compounds that can modulate NADP(+)-dependent oxidation of cortisol by type 1 11beta-hydroxysteroid dehydrogenase (11betaHSD). The objective of this study was to investigate the relationships between levels of the ovarian modulators of type 1 11betaHSD, intra-follicular cortisol:cortisone ratios and the clinical outcome of IVF cycles. METHODS: A single random sample of FF was aspirated from each of 132 patients undergoing gonadotrophin-stimulated IVF. Components of FF, resolved using C18 column chromatography, were evaluated for effects on NADP(+)-dependent cortisol oxidation in rat kidney homogenates. Intra- follicular steroid concentrations were measured by radioimmunoassays. Clinical pregnancies were confirmed by ultrasonography at 6 weeks post-embryo transfer. RESULTS: Levels of the hydrophilic ovarian 11betaHSD stimuli were significantly lower (P<0.0001) and levels of the hydrophobic ovarian 11betaHSD inhibitors were significantly higher (P<0.002) in conception versus non-conception cycles. Intra-follicular cortisol:cortisone ratios increased with the degree of inhibition of 11betaHSD by the hydrophobic FF fractions. FF obtained from conception cycles had significantly higher cortisol:cortisone ratios than samples from non-conception cycles (12.9+/-0.3 versus 8.5+/-0.2, respectively; P<0.0001). CONCLUSIONS: Conception by IVF is associated with elevated intra-follicular cortisol:cortisone ratios, which reflect low levels of ovarian stimuli and/or high levels of ovarian inhibitors of type 1 11betaHSD.
Thurston LM, Chin E, Jonas KC, et al., 2003, Expression of 11beta-hydroxysteroid dehydrogenase (11betaHSD) proteins in luteinizing human granulosa-lutein cells., J Endocrinol, Vol: 178, Pages: 127-135, ISSN: 0022-0795
In a range of tIssues, cortisol is inter-converted with cortisone by 11beta-hydroxysteroid dehydrogenase (11betaHSD). To date, two isoforms of 11betaHSD have been cloned. Previous studies have shown that human granulosa cells express type 2 11betaHSD mRNA during the follicular phase of the ovarian cycle, switching to type 1 11betaHSD mRNA expression as luteinization occurs. However, it is not known whether protein expression, and 11betaHSD enzyme activities reflect this reported pattern of mRNA expression. Hence, the aims of the current study were to investigate the expression and activities of 11betaHSD proteins in luteinizing human granulosa-lutein (hGL) cells. Luteinizing hGL cells were cultured for up to 3 days with enzyme activities (11beta-dehydrogenase (11betaDH) and 11-ketosteroid reductase (11 KSR)) and protein expression (type 1 and type 2 11betaHSD) assessed on each day of culture. In Western blots, an immunopurified type 1 11betaHSD antibody recognized a band of 38 kDa in hGL cells and in human embryonic kidney (HEK) cells stably transfected with human type 1 11betaHSD. The type 2 11betaHSD antibody recognized a band of 48 kDa in HEK cells transfected with human type 2 11betaHSD cDNA but the type 2 protein was not expressed in hGL cells throughout the 3 days of culture. While the expression of type 1 11betaHSD protein increased progressively by 2.7-fold over 3 days as hGL cells luteinized, both 11betaDH and reductase activities declined (by 52.9% and 34.2%; P<0.05) over this same period. Changes in enzyme expression and activity were unaffected by the suppression of ovarian steroid synthesis.
Thurston LM, Jonas KC, Abayasekara DRE, et al., 2003, Ovarian modulators of 11beta-hydroxysteroid dehydrogenase (11beta HSD) activity in follicular fluid from bovine and porcine large antral follicles and spontaneous ovarian cysts., Biol Reprod, Vol: 68, Pages: 2157-2163, ISSN: 0006-3363
In the ovary, cortisol is oxidized to cortisone by 11beta-hydroxysteroid dehydrogenase (11betaHSD). The present study investigated whether follicular fluid (FF) from large antral follicles and spontaneous ovarian cysts, isolated from bovine and porcine ovaries, contained modulators of 11betaHSD activity. Whereas FF from antral follicles had no significant effect over 1 h on NADP+-dependent 11betaHSD activity in rat kidney homogenates, enzyme activity was inhibited by FF from bovine and porcine ovarian cysts (80.5% +/- 2.3% and 72.8% +/- 3.4% of control, respectively). Following C18 reverse-phase chromatography, the hydrophilic fractions of FF from bovine and porcine antral follicles stimulated NADP+-dependent 11betaHSD activities (111.5% +/- 21.6% and 55.2% +/- 5.7% respectively). Hydrophobic compounds inhibited NADP+-dependent cortisol oxidation by 58.2% +/- 5.1% (bovine) and 45.7% +/- 2.0% (porcine). In both species, FF from ovarian cysts appeared to contain less of the hydrophilic stimuli to 11betaHSD activity and more of the hydrophobic inhibitors. The FF from antral follicles and ovarian cysts, and the C18 fractions thereof, had no significant effect on NAD+-dependent cortisol oxidation. The ovarian modulators of NADP+-dependent 11betaHSD activities did not coelute with cortisol, cortisone, estradiol, testosterone, progesterone, pregnenolone, and cholesterol. However, the 11betaHSD stimuli in porcine FF from both antral follicles and cysts coeluted with prostaglandin (PG) E2 and PGF2alpha. We conclude that large antral follicles and spontaneous ovarian cysts, in both the cow and the pig, contain ovarian modulators of the NADP+-dependent 11betaHSD activity. Moreover, FF from spontaneous ovarian cysts, because of decreased content of the 11betaHSD stimulus accompanied by increased content of the 11betaHSD inhibitors, exerts a net inhibitory effect on 11betaHSD activity.
Thurston LM, Norgate DP, Jonas KC, et al., 2002, Ovarian modulators of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity in follicular fluid from gonadotrophin-stimulated assisted conception cycles., Reproduction, Vol: 124, Pages: 801-812, ISSN: 1470-1626
In the ovary, cortisol-cortisone interconversion is catalysed by isoforms of 11beta-hydroxysteroid dehydrogenase (11betaHSD). The objective of this study was to establish whether human follicular fluid (hFF), obtained after controlled ovarian hyperstimulation, contains paracrine modulators of 11betaHSD activity. Of 274 hFF samples tested for effects in rat kidney homogenates, 206 hFF samples significantly inhibited NADP(+)-dependent oxidation of cortisol within 1 h (by 11-67% of control 11betaHSD activity), whereas 42 hFF samples significantly stimulated 11betaHSD activity (16-210% increase relative to control). Although charcoal-stripping of hFF prevented the inhibition and potentiated the stimulation of NADP(+)-dependent cortisol oxidation in a renal homogenate, effects of individual hFF samples on NADP(+)-dependent cortisol oxidation were independent of intrafollicular progesterone concentrations. Hydrophilic fractions of hFF samples, isolated by C18 column chromatography, stimulated both the NADP(+)-dependent oxidation of cortisol (by 55+/-5%, n=98) and the NADPH-dependent reduction of cortisone (by 86+/-22%, n= 5). In contrast, the hydrophobic fractions of hFF (eluted at 65-85% methanol) inhibited both NADP(+)-dependent 11beta-dehydrogenase and NADPH-dependent 11-ketosteroid reductase activities (by 63+/-2% and 74+/-4%, respectively). None of the C18 column fractions of 50 hFF samples had any significant effect on NAD(+)-dependent 11beta-dehydrogenase activities. The hydrophobic inhibitors of NADP(H)-dependent cortisol-cortisone metabolism did not co-elute with several candidate compounds (prostaglandins E(2) and F(2alpha), cortisol, cortisone, oestradiol, testosterone, progesterone, pregnenolone or cholesterol). Hence, hFF aspirated from women undergoing controlled ovarian hyperstimulation for assisted conception contains both hydrophilic stimuli and hydrophobic inhibitors of glucocorticoid metabolism which appear to be selective for the NADP(H)-dependent, typ
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