Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis

Papadopoulos, Vassilios; Amri, Hakima; Boujrad, Noureddine; Cascio, Caterina; Culty, Martine; Garnier, Martine; Hardwick, Matthew; Li, H.; Vidić, Branislav; Brown, Andrea; Reversa, J.L.; Bernassau, Jean‐Marie; Drieu, Katy

doi:10.1016/s0039-128x(96)00154-7

Cited by 353 publications

(299 citation statements)

References 52 publications

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“…S3). The TSPO is proposed to translocate cholesterol from the outer to the inner mitochondrial membrane for downstream synthesis of all steroids in the peripheral tissues, but in the CNS the end products are primarily neurosteroids (24)(25)(26). Earlier, TSPO ligands were shown to have antinociceptive and antiinflammatory effects (27,28 (29)(30)(31).…”

Section: Inhibitors Of Seh Have Cox2-independent Antihyperalgesic Effmentioning

confidence: 99%

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Inceoglu¹,

Jinks

Ulu³

et al. 2008

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

169

218

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During inflammation, a large amount of arachidonic acid (AA) is released into the cellular milieu and cyclooxygenase enzymes convert this AA to prostaglandins that in turn sensitize pain pathways. However, AA is also converted to natural epoxyeicosatrienoic acids (EETs) by cytochrome P450 enzymes. EET levels are typically regulated by soluble epoxide hydrolase (sEH), the major enzyme degrading EETs. Here we demonstrate that EETs or inhibition of sEH lead to antihyperalgesia by at least 2 spinal mechanisms, first by repressing the induction of the COX2 gene and second by rapidly up-regulating an acute neurosteroid-producing gene, StARD1, which requires the synchronized presence of elevated cAMP and EET levels. The analgesic activities of neurosteroids are well known; however, here we describe a clear course toward augmenting the levels of these molecules. Redirecting the flow of pronociceptive intracellular cAMP toward up-regulation of StARD1 mRNA by concomitantly elevating EETs is a novel path to accomplish pain relief in both inflammatory and neuropathic pain states.cAMP ͉ inflammatory pain ͉ steroidogenesis

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Section: Inhibitors Of Seh Have Cox2-independent Antihyperalgesic Effmentioning

confidence: 99%

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Inceoglu¹,

Jinks

Ulu³

et al. 2008

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

169

218

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“…Hence, a role for STC in this context should not be ruled out. Also, it remains to be seen whether STC and its receptor play a role in mitochondrial cholesterol transport in a manner similar to that of the peripheral type benzodiazepine receptor (27)(28)(29).…”

Section: Figmentioning

confidence: 99%

Targeting of Big Stanniocalcin and Its Receptor to Lipid Storage Droplets of Ovarian Steroidogenic Cells

Paciga

McCudden

Londos

et al. 2003

Journal of Biological Chemistry

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Stanniocalcin (STC) is a large polypeptide hormone that is widely distributed in tissues such as kidney, adrenal, and ovary. In most tissues, STC exists as a 50-kDa homodimer (STC 50 ). The ovaries produce a higher molecular weight variant (big STC) in androgen-producing theca cell and interstitial cell compartments. Luteal cells, which do not express the STC gene, nonetheless contain high levels of STC protein, suggesting they are targeted by and sequester big STC through a receptor-mediated process. Recently, an STC⅐alkaline phosphatase fusion protein was used to characterize mitochondrial targeting and sequestration of STC 50 and its receptor in liver and kidney. The main objective of the present study was to characterize big STC and its receptor in mammalian ovary and determine whether the ovarian STC variant was similarly targeted to luteal cell mitochondria. By in situ ligand binding, we identified large numbers of STC receptors on corpus luteal cells. However, a more detailed analysis of sub-cellular fractions revealed that both STC and its receptor were not preferentially targeted to mitochondria but instead to cholesterol/lipid storage droplets, which was more indicative of a role in steroidogenesis. Functional studies revealed that additions of big STC had concentration-dependent inhibitory effects on both basal and stimulated progesterone output by primary cultured luteal cells. Furthermore, STC receptor levels were upregulated in luteal cells in response to protein kinase A activation. Taken together, these findings indicate that theca cell-derived big STC is targeted to the cholesterol/ lipid storage droplets of luteal cells to regulate steroidogenesis. This constitutes the first reported description of polypeptide hormone and receptor targeting to cholesterol/lipid droplets and the first biological role for the big STC variant.The hormone stanniocalcin (STC) 1 is widely distributed in mammalian tissues and for the most part functions locally, because STC is not normally found in the blood. In most tissues, STC exists as a 50-kDa homodimer known as STC 50 . This form of the hormone has a unique signaling pathway whereby it is heavily sequestered by its target cells. In liver and kidney, for instance, STC 50 is first sequestered by target cells and then traffics to their mitochondria where it increases the rate of electron transport. Because STC receptors are present on both the plasma membranes and the mitochondria of target cells, the whole process appears to be receptor-mediated.By far the highest levels of STC gene expression are observed in the ovary (1), where the transcript is confined to theca and interstitial cells (TIC). Interestingly, STC protein is found not only in TICs but also in oocytes and cells of the corpus luteum (1), suggesting that the STC is produced by TICs for targeting to oocytes and luteal cells. The fact that the protein is readily detectable in cells that do not make the hormone further suggests that, as in the case of STC 50 signaling in liver and kidney (2), ovarian STC...

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“…The PBR is believed to be involved in modulating immune response [11], porphyrin transport and heme synthesis [12], regulation of cell proliferation [13], steroid biosynthesis [7,[14][15][16] and programmed cell death [17]. Of these, the most documented functional role of the PBR is its apparent association with steroidogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Molecular modelling of mouse 18-kDa PBR protein was performed under the condition that the five transmembrane domains of the PBR were modelled as five α-helices spanning the outer mitochondrial membrane. This model was evaluated as a cholesterol carrier and it was found that the PBR can house a cholesterol molecule and act as a channel [15]. These results together with in vitro functional assays indicate that the PBR plays a vital role in the transportation of cholesterol from the outer to inner mitochondrial membrane which is known to be the rate limiting step of steroid biosynthesis [18].…”

Section: Introductionmentioning

confidence: 99%

Development of Ligands for the Peripheral Benzodiazepine Receptor

James¹,

Selleri²,

Kassiou

2006

CMC

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Abstract:The peripheral benzodiazepine receptor (PBR) initially characterised as a high affinity binding site for diazepam, is densely distributed in most peripheral organs whilst only moderately expressed in the healthy brain. The predominant cell type expressing the PBR at regions of central nervous system (CNS) pathology are activated microglial cells. Under neuroinflammatory conditions there is an over-expression of PBR binding sites indicating that measurements of PBR density can act as a useful index of brain disease activity. The PBR is now considered a significant therapeutic and diagnostic target which has provided the impetus for PBR ligand development. There are several classes of PBR ligands available including benzodiazepines (Ro5 -4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106) and pyrazolopyrimidines (DPA-713). Subsequent conformationally restrained isoquinoline and indoleacetamide analogues have been synthesised in an attempt to yield PBR ligands with superior affinity and brain kinetics. Even though the PBR has been linked to a number of biochemical processes, including cell proliferation, apoptosis, steroidogenesis, porphyrin transport and immunomodulation, its exact physiological role is yet to be deciphered. Selective PBR ligands with favourable in vivo binding properties and kinetics is required to gain a more complete understanding on the normal functioning of the PBR and the chemical pathways underlying several pathological conditions. Novel PBR ligands with unique binding properties and functional activity may also generate information on the localisation of the PBR and the possibility of PBR subtypes. This review highlights the main classes of PBR ligands to date. In addition the biological activity and therapeutic potential of certain PBR ligands is discussed.

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Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis

Cited by 353 publications

References 52 publications

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Targeting of Big Stanniocalcin and Its Receptor to Lipid Storage Droplets of Ovarian Steroidogenic Cells

Development of Ligands for the Peripheral Benzodiazepine Receptor

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