A new function for CD38/ADP-ribosyl cyclase in nuclear Ca2+ homeostasis

Adebanjo, OA; Hk, Anandatheerthavarada; Ap, Koval; Moonga, Baljit S.; Biswas, Gopa; Sun, Liyuan; Br, Sodam; Pj, Bevis; Cl, Huang; Epstein, Solomon; Lai, F. Anthony; Ng, Avadhani; Zaidi, Mone

doi:10.1038/15640

Cited by 158 publications

(144 citation statements)

References 27 publications

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“…To exclude potential artifacts arising from the extreme flatness of cultured cells or possible localization of Avpr1αs to membrane structures close to the nuclear compartment, we isolated intact nucleoplasts from primary murine osteoblasts. This method removes the outer nuclear membrane, providing pure fractions of nucleoplasts surrounded by the inner but not the outer nuclear membrane (19). Nucleoplasts were isolated after stimulation of intact osteoblasts with Avp (30 min) and were stained for Avp and importin-β (Kpnb1), a known inner nuclear membrane and nucleoplasm marker.…”

Section: Resultsmentioning

confidence: 99%

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Functions of vasopressin and oxytocin in bone mass regulation

Sun

Tamma

Yuen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr −/− mice have osteopenia, and Avpr1α −/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr −/− :Avpr1α −/− doublemutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avpstimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α −/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.O ver the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1-8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts. We also find that the skeleton is highly sensitive to the action of posterior pituitary hormones; for example, mice haploinsufficient in oxytocin (Oxt) have osteopenic bones, but lactation is normal; lactation is impaired only in Oxt −/− mice (2). Likewise, Tshr haploinsufficient mice are completely euthyroid with normal thyroid follicles but display significant osteopenia (4). The exquisite sensitivity of the skeleton to pituitary hormones comes as no surprise, considering that the pituitary gland and the skeleton are both evolutionarily more primitive than target endocrine organs (7).Apart from the known actions of growth hormone on the skeleton, Tsh, Fsh, Acth, Oxt, and vasopressin (Avp) have all been shown to regulate the formation and/or function of both osteoblasts and osteoclasts and thus to control bone remodeling in vivo (2-4, 6-8). The two neurohypophyseal hormones Oxt and Avp have opposing functions (2, 3). Oxt stimulates and Avp inhibits osteoblast formation. Consequently, the genetic deletion of the Oxt receptor (Oxtr) and Avp receptor 1α (Avpr1α) yields opposing phenotypes, notably osteopenia in Oxtr −/− mice and high bone mass in Avpr1α −/− mice (2, 3). These findings may explain the rapid recovery of bone loss at weaning when plasma Oxt levels are high (9) and also the profound loss of bone noted in chronic hyponatremic states, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in which serum Avp levels are elevated (3).We find high levels of Oxtr expression on ...

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Section: Resultsmentioning

confidence: 99%

“…For the preparation of nucleoplasts, osteoblast-enriched cultures were obtained by sequential collagenase digestion of newborn calvaria. Intact nuclei were isolated as described by Adebanjo et al (19). The outer nuclear membrane and nucleoplasts (nuclei without outer membranes) were separated.…”

Section: Methodsmentioning

confidence: 99%

Functions of vasopressin and oxytocin in bone mass regulation

Sun

Tamma

Yuen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, the ADP-ribosyl cyclase enzyme that is responsible for the production of cyclic ADP ribose (cADPR) and/or NAADP is localised in the nucleus (Adebanjo et al, 1999;Bezin et al, 2008a;Trubiani et al, 2008). In addition, it has been well established that nuclei possess phosphoinositide signalling mechanisms that are similar to, but distinct from, those that occur at the plasma membrane, and which can lead to InsP 3 production (Visnjic and Banfic, 2007;Ye and Ahn, 2008).…”

Section: Autonomous Generation Of Ca 2+ -Mobilising Messengers In Thementioning

confidence: 99%

An update on nuclear calcium signalling

Bootman

Fearnley

Smyrnias

et al. 2009

Journal of Cell Science

189

194

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Over the past 15 years or so, numerous studies have sought to characterise how nuclear calcium (Ca 2+ ) signals are generated and reversed, and to understand how events that occur in the nucleoplasm influence cellular Ca 2+ activity, and vice versa. In this Commentary, we describe mechanisms of nuclear Ca 2+ signalling and discuss what is known about the origin and physiological significance of nuclear Ca 2+ transients. In particular, we focus on the idea that the nucleus has an autonomous Ca 2+ signalling system that can generate its own Ca 2+ transients that modulate processes such as gene transcription. We also discuss the role of nuclear pores and the nuclear envelope in controlling ion flux into the nucleoplasm. Journal of Cell Science 2338(which would cause its nuclear export) and through a physical interaction that occludes a nuclear-export sequence (NES) in the NFAT protein.An example of a nuclear-localised transcription factor that is regulated by both nuclear and cytosolic Ca 2+ signals is cyclic AMP response element-binding protein (CREB). The signalling mechanisms that underlie CREB activation have been worked out particularly well in neurons, in which it has been established that depolarisation leads to the rapid phosphorylation of CREB on Ser133 by Ca 2+ -calmodulin-dependent kinase IV, which provides a necessary, but not sufficient, signal for CREB-mediated gene transcription (Dolmetsch et al., 2001). The triggering event is an increase in cytosolic Ca 2+ levels in the immediate vicinity of L-type Ca 2+ channels or N-methyl-D-aspartate receptors that are found in the synapse, at a site that is distal to the nucleus (Shaywitz and Greenberg, 1999). As CREB is only found in the nucleus, the phosphorylation of Ser133 is mediated by one of several Ca 2+ -sensitive signal transduction cascades that convey information from the remote synapses into the nucleus. In the nucleus, phosphorylated CREB binds additional proteins to form a transcriptionally active complex (Shaywitz and Greenberg, 1999). Although the synaptic Ca 2+ signal does not need to propagate to the nucleus to induce phosphorylation of Ser133 on CREB, an increase in the level of nuclear Ca 2+ is required for CREB-mediated gene transcription to occur. This is because additional Ca 2+ -dependent phosphorylation of CREB and its co-activators is required (Chawla et al., 1998;Kornhauser et al., 2002). Indeed, nuclear injection of an artificial Ca 2+ buffer prevents CREB-mediated gene transcription, but not transcription induced by the serum-response element, which is sensitive to cytosolic Ca 2+ buffering (Hardingham et al., 1997).Another well-known target of nuclear Ca 2+ signalling is the transcriptional regulator downstream regulatory element antagonist modulator (DREAM). It is well established that DREAM represses the expression of prodynorphin, an opiate-receptor precursor, and that mice that lack DREAM have a constitutive analgesic condition (Cheng et al., 2002). DREAM contains four Ca 2+ -binding EF hands (a widely expressed structural mo...

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“…CD38 is found on the plasma membrane and in multiple organelles, including the nucleus (29)(30)(31). CD38 is known to favor the production of NAADP over cADPr at acidic pHs or in the presence of cAMP and may require endocytosis, suggesting its subcellular location may be important (32,33).…”

Section: Naadp-sensitive Camentioning

confidence: 99%

Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells

Johnson

Misler

2002

Proc. Natl. Acad. Sci. U.S.A.

133

138

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Recent studies suggest a role for autocrine insulin signaling in beta cells, but the mechanism and function of insulin-stimulated Ca 2؉ signals is uncharacterized. We examined Ca 2؉ -dependent insulin signaling in human beta cells. calcium signals ͉ ryanodine ͉ autocrine ͉ CD38 ͉ diabetes mellitus D iscovery of insulin receptors on pancreatic beta cells and the characterization of beta cell-specific insulin receptor null mice with a diabetes-like phenotype suggest a physiological role for autocrine insulin signaling (1). Although results from in vivo and whole islet experiments suggested a negligible or inhibitory effect of insulin on insulin release, recent experiments with dispersed rodent beta cells suggested a stimulatory effect on calcium signaling, insulin expression, and exocytosis (2-7). Unlike glucose signaling, insulin-evoked Ca 2ϩ signals in mouse beta cells required intracellular Ca 2ϩ stores sensitive to the sarcoplasmic͞endoplasmic Ca 2ϩ -ATPase (SERCA) inhibitor thapsigargin (4). Insulin action was not blocked by a phospholipase C inhibitor, suggesting indirectly that inositol 1,4,5-trisphosphate (IP 3 )-sensitive Ca 2ϩ stores were not involved (5). The mechanisms of autocrine insulin feedback are unknown in human beta cells.Ca 2ϩ signals control multiple functions in secretory cells, and at least three distinct biochemical classes of Ca 2ϩ stores coexist (8, 9). Aside from the phospholipase C͞IP 3 pathway that is commonly activated by G-protein-coupled receptors, Ca 2ϩ can be mobilized through ryanodine receptors, activated by Ca 2ϩ or cyclic ADP-ribose (cADPr). A third class of Ca 2ϩ store, mobilized by nicotinic acid adenine dinucleotide phosphate (NAADP), functions in oocytes, Jurkat T lymphocytes, and mouse pancreatic acini (8, 10, 11). The production of NAADP and cADPr are catalyzed by CD38 and related ADP-ribosyl cyclases (12, 13). CD38 is found in many cell types, including human beta cells. Glucose-stimulated Ca 2ϩ mobilization and insulin release (in vivo and in vitro) were enhanced by CD38 overexpression and reduced by CD38 knockout (14,15). Beta cells with poor glucose-stimulated insulin production͞release (ob͞ob, GK, RINm5F) have less CD38 (16,17). CD38 autoantibodies, found in Ϸ14% of diabetic patients, evoked Ca 2ϩ signals and insulin release from human islet cells (18).In this study, we tested the hypothesis that NAADP-sensitive Ca 2ϩ stores regulate beta cell function, in the context of autocrine insulin signaling. We report that insulin generates complex Ca 2ϩ signals by mobilizing novel intracellular Ca 2ϩ stores in primary cultures of dispersed human islet cells. NAADPsensitive Ca 2ϩ stores initiate insulin signaling, whereas subsequent oscillatory behavior is sensitive to the removal of extracellular Ca 2ϩ and to putative IP 3 receptor inhibitors. These prolonged insulin-stimulated Ca 2ϩ signals regulate cellular insulin levels, but do not measurably stimulate overall secretion. Materials and MethodsDrugs and Solutions. Reagents were from Sigma unless otherwise stated. Stocks ...

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A new function for CD38/ADP-ribosyl cyclase in nuclear Ca2+ homeostasis

Cited by 158 publications

References 27 publications

Functions of vasopressin and oxytocin in bone mass regulation

Functions of vasopressin and oxytocin in bone mass regulation

An update on nuclear calcium signalling

Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells

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