Identification of a Membrane Receptor for 1,25-Dihydroxyvitamin D3 Which Mediates Rapid Activation of Protein Kinase C

Nemere, Ilka; Schwartz, Zvi; Pedrozo, H. A.; Sylvia, V. L.; Dean, David D.; Boyan, Barbara D.

doi:10.1359/jbmr.1998.13.9.1353

Cited by 207 publications

(122 citation statements)

References 44 publications

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“…At a different level, 1,25D regulates the expression of tissue-specific genes via a nuclear vitamin D receptor (VDR) that functions as a transcription factor (4,5). Although these two mechanisms of action are known to occur through different signaling pathways, there is no clear consensus yet whether rapid, membrane-related actions of 1,25D are initiated by a unique membrane receptor of unknown molecular identity or whether the classic VDR is involved (6)(7)(8)(9).…”

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Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

Zanello

Norman²

2004

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

143

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1␣,25(OH)2-Vitamin D3 (1,25D) modulates osteoblast gene expression of bone matrix proteins via a nuclear vitamin D receptor (VDR) and also modifies the electrical state of the plasma membrane through rapid nongenomic mechanisms still not fully understood. The physiological significance of 1,25D membrane-initiated effects remains unclear. To elucidate whether the VDR is required for 1,25D-promoted electrical responses, we studied 1,25D modulation of ion channel activities in calvarial osteoblasts isolated from VDR knockout (KO) and WT mice. At depolarizing potentials, Cl ؊ currents were significantly potentiated (13.5 ؎ 1.6-fold increase, n ‫؍‬ 12) by 5 nM 1,25D in VDR WT but not in KO (0.96 ؎ 0.3 fold increase, n ‫؍‬ 11) osteoblasts. L-type Ca 2؉ currents significantly shift their peak activation by ؊9.3 ؎ 0.7 mV (n ‫؍‬ 10) in the presence of 5 nM 1,25D in VDR WT but not in KO cells, thus facilitating Ca 2؉ influx. Furthermore, we found that 1,25D significantly increased wholecell capacitance in VDR WT (⌬Cap ‫؍‬ 2.3 ؎ 0.4 pF, n ‫؍‬ 8) but not in KO osteoblasts (⌬Cap ‫؍‬ 0.3 ؎ 0.1 pF, n ‫؍‬ 8); this corresponds to a rapid (1-2 min) fusion in WT of 71 ؎ 33 versus in KO only 9 ؎ 6 individual secretory granules. We conclude that, in calvarial osteoblasts, 1,25D modulates ion channel activities only in cells with a functional VDR and that this effect is coupled to exocytosis. This is a demonstration of the requirement of a functional classic steroid receptor for the rapid hormonal modulation of electric currents linked to secretory activities in a target cell.N ongenomic responses to the steroid 1␣,25(OH) 2 -vitamin D 3 (1,25D) develop at the plasma membrane of various target cells and comprise rapid (seconds to minutes) changes in ion channel activities, activation of second messenger pathways, and elevation of cytosolic calcium concentrations (1-3). At a different level, 1,25D regulates the expression of tissue-specific genes via a nuclear vitamin D receptor (VDR) that functions as a transcription factor (4, 5). Although these two mechanisms of action are known to occur through different signaling pathways, there is no clear consensus yet whether rapid, membrane-related actions of 1,25D are initiated by a unique membrane receptor of unknown molecular identity or whether the classic VDR is involved (6-9).In bone, 1,25D elicits physiological responses at both the genomic and nongenomic levels. Osteoblasts, which are secretory cells, produce a variety of bone matrix proteins and actively participate in the mineralization process under the influence of hormones involved in mineral metabolism, such as 1,25D. Recently, several strains of functional VDR knockout (KO) mice have been created by means of deletion of selected portions of the VDR gene (10-13). They constitute a valuable tool for the study of a vast range of physiological conditions that arise from an impaired 1,25D physiology. Nuclear VDR KO mice, with abrogated 1,25D genomic actions, develop a genotype typical of rickets type II, characterized by decreased...

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Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

Zanello

Norman²

2004

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

143

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“…The two current cell models bearing point mutations at key sites of the encoded VDR gene offer unique contributions to these challenging research fields. First, the current controversy over the presence and role of a distinct VDR membrane receptor is based on data obtained by different research teams using different cell models and different assays to test the rapid responses to 1,25-(OH) 2 D 3 (7,18,22). In the present work, cell type, skin fibroblasts from agematched children, and culture conditions were identical, as was the biological test used for rapid 1,25-(OH) 2 D 3 response, namely modification of intracellular calcium in Fura-2-loaded cells.…”

Section: Discussionmentioning

confidence: 99%

“…These effects include activation of the phospholipase C pathway via G␣ q/11 (8, 9), activation of the adenylate cyclase pathway (10), opening of voltage-gated Ca 2ϩ channels (L-type) in the plasma membrane (11, 12), Ca 2ϩ mobilization from the endoplasmic reticulum (5), and an increase in cyclic guanosine monophosphate levels (13). The rapid effects of 1,25-(OH) 2 D 3 also include the activation of the mitogenactivated protein kinase (MAPK) pathway (14 -16), which induces a cross-talk with the cell nucleus via phosphorylation of cytoplasmic kinases and nuclear transcription factors (7,16,17).Attempts have been made to identify the receptor mediating the non-classical rapid effects of 1,25-(OH) 2 D 3 , but the data are still controversial (7,18,19). A first set of data supports the hypothesis that VDR itself mediates 1,25-(OH) 2 D 3 rapid effects.…”

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The Rapid Effects of 1,25-Dihydroxyvitamin D3 Require the Vitamin D Receptor and Influence 24-Hydroxylase Activity

Nguyen

Lieberherr²,

Fritsch

et al. 2004

Journal of Biological Chemistry

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If both rapid and genomic pathways may co-exist in the same cell, the involvement of the nuclear vitamin D receptor (VDR) in the rapid effects of 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) remains unclear. We therefore studied rapid and long term effects of 1,25-(OH) 2 D 3 in cultured skin fibroblasts from three patients with severe vitamin D-resistant rickets and one age-matched control. Patients bear homozygous missense VDR mutations that abolished either VDR binding to DNA (patient 1, mutation K45E) or its stable ligand binding (patients 2 and 3, mutation W286R). In patient 1 cells, 1,25-(OH) 2 D 3 (1 pM-10 nM) had no effect on either intracellular calcium or 24-hydroxylase (enzyme activity and mRNA expression). In contrast, cells bearing the W286R mutation had calcium responses to 1,25-(OH) 2 D 3 (profile and magnitude) and 24-hydroxylase responses to low (1 pM-100 pM) 1,25-(OH) 2 D 3 concentrations (activity, CYP24, and ferredoxin mRNAs) similar to those of controls. The blocker of Ca 2؉ channels, verapamil, impeded both rapid (calcium) and long term (24-hydroxylase activity, CYP24, and ferredoxin mRNAs) responses in patient and control fibroblasts. The MEK 1/2 kinase inhibitor PD98059 also blocked the CYP24 mRNA response. Taken together, these results suggest that 1,25-(OH) 2 D 3 rapid effects require the presence of VDR and control, in part, the first step of 1,25-(OH) 2 D 3 catabolism via increased mRNA expression of the CYP24 and ferredoxin genes in the 24-hydroxylase complex.The general and severe end organ resistance to vitamin D observed in patients with mutations in the gene encoding the nuclear vitamin D receptor (VDR) 1 bring forth strong evidence that most cellular actions of 1,25-(OH) 2 D 3 , the hormonal form of vitamin D, are mediated through interactions of the hormone with its nuclear receptor (1). The VDR, which belongs to the steroid/thyroid nuclear receptor family, is composed of two principal domains, one domain for hormone binding (exons 6 -9) and one domain for DNA binding (exons 2 and 3, coding for two zinc fingers) (2). Although most classical effects of 1,25-(OH) 2 D 3 involve this genomic pathway, several other effects may be observed very rapidly, within seconds to minutes, and are not blocked by inhibitors of transcription or translation, suggesting a more direct action of the hormone at the membrane level (3-7). These effects include activation of the phospholipase C pathway via G␣ q/11 (8, 9), activation of the adenylate cyclase pathway (10), opening of voltage-gated Ca 2ϩ channels (L-type) in the plasma membrane (11, 12), Ca 2ϩ mobilization from the endoplasmic reticulum (5), and an increase in cyclic guanosine monophosphate levels (13). The rapid effects of 1,25-(OH) 2 D 3 also include the activation of the mitogenactivated protein kinase (MAPK) pathway (14 -16), which induces a cross-talk with the cell nucleus via phosphorylation of cytoplasmic kinases and nuclear transcription factors (7,16,17).Attempts have been made to identify the receptor mediating the non-classical r...

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“…De plus, l'utilisation d'inhibiteurs de la transcription génique et de la synthèse protéique n'inhibe pas tous les effets musculaires de la vitamine D. Ces données indiquent que la 1,25(OH) 2 vitamine D peut agir directement sur la membrane des cellules musculaires, en particulier au niveau des radeaux lipidiques, sans influencer l'expression génique (Boland, 2011 ;Buitrago, 2012Buitrago, , 2013Nemere, 1994Nemere, , 1998. Ainsi, le traitement de cellules musculaires en culture par la 1,25(OH) 2 vitamine D, provoque l'activation de seconds messagers interagissant dans différentes voies régulatrices intracellulaires et induisant une augmentation de l'absorption du calcium (en quelques minutes), à travers les canaux calciques voltage-dépendants (De Bolland, 1994 ;Massheimer, 1992 ;Vazquez, 1997).…”

Section: Les Mécanismes Mis En Jeuunclassified

Les effets musculaires de la vitamine D : application à la perte musculaire liée à l’âge

Walrand¹

2014

Cahiers de Nutrition et de Diététique

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Résumé -Au-delà de ses rôles biologiques classiques sur la santé osseuse, les effets extra-squelettiques de la vitamine D font actuellement l'objet de nombreuses recherches. La présence du récepteur de la vitamine D dans la plupart des tissus de l'organisme vient d'ailleurs renforcer l'argument en faveur de ses fonctions multiples. Parmi celles-ci, l'effet de la vitamine D sur la masse et les performances musculaires a été longtemps pressenti. En effet, dans la Grèce Antique, Hérodote recommandait le soleil comme un remède pour les « muscles faibles et mous », et les anciens Olympiens recevaient l'ordre de se coucher exposés aux rayons du soleil pour améliorer leurs performances physiques. En 1952, Spellerberg, un physiologiste du sport, a réalisé une vaste étude portant sur les effets de l'irradiation UV sur les performances d'athlètes de haut niveau. Suite aux résultats positifs de cette investigation, ce scientifique dû informer le Comité Olympique que l'irradiation UV présentait un effet « convaincant » sur la performance physique et les capacités motrices. Ces données sont conformes à de nombreuses études postérieures signalant une amélioration des aptitudes physiques, de la vitesse et de l'endurance chez des sujets jeunes traités par des UV ou par des suppléments contenant de la vitamine D. Des observations complémentaires font état d'un effet significatif sur la force musculaire, en particulier au niveau des membres inférieurs. Concernant les mécanismes mis en jeu, certaines études fondamentales récentes ont montré que la vitamine D exerce des effets moléculaires au sein de la cellule musculaire. Précisément, une action régulatrice de la vitamine D sur les flux de calcium, l'homéostasie minérale et certaines voies de signalisation contrôlant l'anabolisme protéique a été rapportée au niveau du tissu musculaire. Plusieurs enquêtes épidémiologiques révèlent qu'un faible statut en vitamine D est toujours associé à une diminution de la masse, de la force et des capacités contractiles musculaires chez la personne âgée. Cette atteinte aboutit à une accélération de la perte musculaire avec l'âge (sarcopénie), et par conséquent à une réduction des capacités physiques et à une augmentation du risque de chute et de fracture. À l'inverse, un apport supplémentaire de vitamine D chez le sujet âgé améliore significativement les paramètres fonctionnels musculaires classiquement recherchés. Mots clés :Vitamine D / muscle squelettique / sarcopénie / sujets âgés Abstract -Beyond its traditional biological roles on bone health, extra-skeletal effects of vitamin D are currently under extensive research. The expression of the vitamin D receptor in most tissues has also strengthened the argument for its multiple functions. Among these, the effect of vitamin D on the mass and muscle performance has long been discussed. In ancient Greece, Herodotus recommended the sun as a cure for the "weak and soft muscles" and former Olympians exposed to sunlight to improve their physical performance. In 1952, Dr Spellerberg, a sports physiolo...

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Identification of a Membrane Receptor for 1,25-Dihydroxyvitamin D3 Which Mediates Rapid Activation of Protein Kinase C

Cited by 207 publications

References 44 publications

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

The Rapid Effects of 1,25-Dihydroxyvitamin D3 Require the Vitamin D Receptor and Influence 24-Hydroxylase Activity

Les effets musculaires de la vitamine D : application à la perte musculaire liée à l’âge

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Identification of a Membrane Receptor for 1,25-Dihydroxyvitamin D3 Which Mediates Rapid Activation of Protein Kinase C

Cited by 207 publications

References 44 publications

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) 2 -vitamin D 3 requires the presence of a functional vitamin D nuclear receptor

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) 2 -vitamin D 3 requires the presence of a functional vitamin D nuclear receptor

The Rapid Effects of 1,25-Dihydroxyvitamin D3 Require the Vitamin D Receptor and Influence 24-Hydroxylase Activity

Les effets musculaires de la vitamine D : application à la perte musculaire liée à l’âge

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Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor