Membrane-mediated actions of 1,25-dihydroxy vitamin D3: A review of the roles of phospholipase A2 activating protein and Ca2+/calmodulin-dependent protein kinase II

Doroudi, Maryam; Schwartz, Zvi; Boyan, Barbara D.

doi:10.1016/j.jsbmb.2014.11.002

Cited by 55 publications

(49 citation statements)

References 33 publications

(39 reference statements)

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“…The VDR is an intracellular/nuclear receptor acting as a classical steroid hormone receptor. Similar to reports describing, rapid nongenomic estrogen, progesterone and testosterone signaling associated with activation of plasma membrane receptors for these steroids, there are reports showing that 1,25D3 may also have binding sites/receptors in the plasma membrane responsible for rapid, non-genomic 1,25D3-stimulated functional effects [17,18]. The rapid 1,25D3-evoked responses involve for example opening of voltage-dependent Ca 2+ channels in osteoblasts and migration of endothelial cells, and they are thought to involve interaction of 1,25D3 with proteins such as protein disulfide isomerase family A member 3, phospholipase A2 and caveolin-1 in the plasma membrane caveolae [18].…”

Section: Vitamin D Signalingsupporting

confidence: 59%

Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production

2015

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The steroid hormone metabolite of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25D3), promotes osteogenic activity and regulates calcium and phosphate metabolism, which are actions regarded as classical vitamin D-regulated functions. Besides its role in these processes, 1,25D3 also seems implicated in the host defense against microbial/proinflammatory attacks. Low serum levels of vitamin D 3 (vitamin D deficiency) are associated with osteoporosis and increased risk of fractures but also inflammatory diseases and their disease progression, presumably via mechanisms associated with 1,25D3-evoked modulation of the innate immune system. 1,25D3 has been reported to modulate many inflammatory responses, suggesting that it regulates multiple transcriptional targets within the inflammatory system. Experimental studies in various experimental systems show that 1,25D3 differentially regulates the production of pro-inflammatory cytokines and chemokines depending on cell type. Importantly, many reports show that 1,25D3 up-regulates expression of the human antimicrobial peptide hCAP-18/LL-37 gene. The hCAP-18/LL-37 gene seems indeed to be an important transcriptional target for 1,25D3. However, only weak evidence is presented showing that 1,25D3 consistently increases the amount of biologically active LL-37 peptide.In the present review, we discuss 1,25D3-induced down-regulation of cytokine/chemokine production and stimulation of hCAP-18/LL-37 gene expression which represent two very important pathways for 1,25D3-evoked regulation of the innate immune response.

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Section: Vitamin D Signalingsupporting

confidence: 59%

Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production

2015

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“…As global knockout of Pdia3 is embryologically lethal, the ability to determine its full impact is hampered. However, chondrocytes isolated from costochondral cartilage of VDR knockout mice and Ca 2+ influx studies in the guts of these mice demonstrate that 1α,25(OH) 2 D 3 still elicits rapid activation of PKC and a biological response [38,39]. Studies using Pdia3 conditional knockout mice [40], Pdia3-silenced osteoblasts [41], and Pdia3 ± heterozygote mice [42] have demonstrated a loss of rapid activation of PKC and release of PGE 2 , decreased osteopontin production and alkaline phosphatase activity, and bone and cartilage abnormalities.…”

Section: Alternative Membrane Receptorsmentioning

confidence: 99%

“…These receptors are hypothesized to elicit activation of G-protein-dependent signaling cascades that are associated with the plasma membrane, mainly the caveolae [37]. In the case of 1α,25(OH) 2 D 3 , membrane-associated protein disulfide isomerase, family A, member 3 (Pdia3), which is recognized as a chaperone protein, also functions as a membrane receptor [38]. Its rapid signaling cascade involves activation of protein kinase C (PKC) and downstream mitogen-activated protein kinase (MAPK) [38].…”

Section: Alternative Membrane Receptorsmentioning

confidence: 99%

“…In the case of 1α,25(OH) 2 D 3 , membrane-associated protein disulfide isomerase, family A, member 3 (Pdia3), which is recognized as a chaperone protein, also functions as a membrane receptor [38]. Its rapid signaling cascade involves activation of protein kinase C (PKC) and downstream mitogen-activated protein kinase (MAPK) [38]. As global knockout of Pdia3 is embryologically lethal, the ability to determine its full impact is hampered.…”

Section: Alternative Membrane Receptorsmentioning

confidence: 99%

“…Arachidonic acid can activate PKC directly through a PLAA mediated pathway or be further metabolized, resulting in PGE 2 production, which then acts through its EP1 receptor leading to MAPK activation. Alternatively, IP 3 stimulates Ca +2 release from the endoplasmic reticulum and activation of PKCα via translocation to the plasma membrane by DAG [38,74] (Fig. 1).…”

Section: Rapid Non-genomic Membrane Signalingmentioning

confidence: 99%

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Rapid steroid hormone actions via membrane receptors

Schwartz

Verma

Bivens

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Steroid hormones regulate a wide variety of physiological and developmental functions. Traditional steroid hormone signaling acts through nuclear and cytosolic receptors, altering gene transcription and subsequently regulating cellular activity. This is particularly important in hormonally-responsive cancers, where therapies that target classical steroid hormone receptors have become clinical staples in the treatment and management of disease. Much progress has been made in the last decade in detecting novel receptors and elucidating their mechanisms, particularly their rapid signaling effects and subsequent impact on tumorigenesis. Many of these receptors are membrane-bound and lack DNA-binding sites, functionally separating them from their classical cytosolic receptor counterparts. Membrane-bound receptors have been implicated in a number of pathways that disrupt the cell cycle and impact tumorigenesis. Among these are pathways that involve phospholipase D, phospholipase C, and phosphoinositide-3 kinase. The crosstalk between these pathways has been shown to affect apoptosis and proliferation in cardiac cells, osteoblasts, and chondrocytes as well as cancer cells. This review focuses on rapid signaling by 17β-estradiol and 1α,25-dihydroxy vitamin D3 to examine the integrated actions of classical and rapid steroid signaling pathways both in contrast to each other and in concert with other rapid signaling pathways. This new approach lends insight into rapid signaling by steroid hormones and its potential for use in targeted drug therapies that maximize the benefits of traditional steroid hormone-directed therapies while mitigating their less desirable effects.

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Tomatidine Reduces Palmitate‐Induced Lipid Accumulation by Activating AMPK via Vitamin D Receptor‐Mediated Signaling in Human HepG2 Hepatocytes

Kusu

Yoshida

Kudo

et al. 2019

Molecular Nutrition Food Res

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Scope Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide, defined by hepatic over‐accumulation of lipids without significant ethanol consumption. Pharmacological or bioactive food ingredients that suppress hepatic lipid accumulation through AMP‐activated protein kinase (AMPK) signaling, which plays a critical role in the regulation of lipid metabolism, are searched. Methods and results It is found that tomatidine, the aglycone of α‐tomatine abundant in green tomatoes, significantly inhibits palmitate‐provoked lipid accumulation and stimulates phosphorylation of AMPK and acetyl‐CoA carboxylase 1 (ACC1) in human HepG2 hepatocytes. The results also indicate that tomatidine can enhance triglyceride turnover and decline in lipogenesis by upregulating adipose triglyceride lipase (ATGL) and downregulating fatty acid synthase (FAS) via the AMPK signaling‐dependent regulation of transcription factors, element‐binding protein‐1c (SREBP‐1c) and forkhead box protein O1 (FoxO1). Furthermore, mechanistic studies demonstrate that tomatidine‐stimulated AMPK phosphorylation is due to CaMKKβ activation in response to an increase in intracellular Ca2+ concentration. Finally, it is discovered that tomatidine functions as an agonist for vitamin D receptor to elicit AMPK‐dependent suppression of lipid accumulation. Conclusion The in vitro study suggests the potential efficacy of tomatidine as a preventive and therapeutic treatment in obesity‐related fatty liver diseases.

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Membrane-mediated actions of 1,25-dihydroxy vitamin D3: A review of the roles of phospholipase A2 activating protein and Ca2+/calmodulin-dependent protein kinase II

Cited by 55 publications

References 33 publications

Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production

Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production

Rapid steroid hormone actions via membrane receptors

Tomatidine Reduces Palmitate‐Induced Lipid Accumulation by Activating AMPK via Vitamin D Receptor‐Mediated Signaling in Human HepG2 Hepatocytes

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