Translocator protein (18 kDa): an update on its function in steroidogenesis

Abstract

about the role of this protein in steroid and heme synthesis. We review the data on the structure and function of TSPO, as well as the recent results obtained using various genetic animal models. Taken together, these studies suggest that TSPO is a unique mitochondrial pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis. Although there is no known mammalian species that lacks TSPO, it is likely that, because of the importance of this ancient protein in evolution and mitochondrial function, redundant mechanisms may exist to replace it under circumstances when it is removed. K E Y W O R D Smitochondria, neuroactive steroids, steroids, translocator protein

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…Moreover, it should be noted that 5 alcohol-dependent subjects took benzodiazepines within 2 days of scanning in this study. Benzodiazepines are known to bind TSPO [144] and thus could influence TSPO availability [145]. However, the author’s reported [ 11 C]PBR28 binding was unaffected among those subjects [143].…”

Endogenous neurosteroids influence synaptic GABAA receptors during postnatal development

“…The schematic illustrates the de novo neurosteroid synthesis. Initially, cholesterol is translocated across the mitochondrial membrane by translocator protein 18 kDa (TSPO) and accessory proteins (eg, VDAC ; the 32‐ kD a voltage‐dependent anion channel [required for benzodiazepine binding]) . The mitochondrial P450scc ( CYP 11A1) converts cholesterol to pregnenolone, which diffuses into the cytosol.…”

“…The enzymes synthesising neurosteroids exhibit regional and cellular‐selective expression patterns, which change within discrete temporal windows and are susceptible to external challenges (eg, stress) . In the CNS, the production of GABA A R‐active neurosteroids from cholesterol (Figure ) first requires the translocation of the steroid across the mitochondrial membrane by translocator protein 18 kDa (TSPO) . Cholesterol is then metabolised to pregnenolone by the mitochondrial P450 side‐chain cleavage enzyme CYP11A1 and this metabolite is then exported across the mitochondrial membrane, where it may be converted to GABA A R‐active neurosteroids such as allopregnanolone following three sequential enzyme reactions catalysed by 3β‐hydroxysteroid dehydrogenase (3β‐HSD) to form progesterone, 5α‐reductase (5α‐R) to produce 5α‐dihydroprogesterone (5α‐DHP) and 3α‐hydroxysteroid dehydrogenase (3α‐HSD) to form allopregnanolone (Figure ) .…”

“…23,[30][31][32][33] In the CNS, the production of GABA A R-active neurosteroids from cholesterol ( Figure 1) first requires the translocation of the steroid across the mitochondrial membrane by translocator protein 18 kDa (TSPO). 34,35 Cholesterol is then metabolised to pregnenolone by the mitochondrial P450 side-chain cleavage enzyme CYP11A1 and this metabolite is then exported across the mitochondrial membrane, where it may be converted to GABA A R-active neurosteroids such as allopregnanolone following three sequential enzyme reactions catalysed by 3β-hydroxysteroid dehydrogenase (3β-HSD) to form progesterone, 5α-reductase (5α-R) to produce 5α-dihydroprogesterone (5α-DHP) and 3α-hydroxysteroid dehydrogenase (3α-HSD) to form allopregnanolone ( Figure 1). 7 Note that, both in the CNS and the periphery, the enzymes 5α-R and 3α-HSD may sequentially participate in the conversion of deoxycorticosterone derived primarily from the adrenals into the GABA A R-active 5α-THDOC.…”

New perspectives for the action of steroids in the brain

“…This is the rate‐limiting step in steroidogenesis. Recent studies have generated controversy concerning the role of this protein in steroid synthesis; however, recent results using various genetic animal models suggest that TSPO is a unique pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis …”