Channel-Like Functions of the 18-kDa Translocator Protein (TSPO): Regulation of Apoptosis and Steroidogenesis as Part of the Host-Defense Response

Abstract

Due to its channel-like properties, the peripheral-type benzodiazepine receptor (PBR) has been renamed the translocator protein (TSPO). In eukaryotes, the TSPO is primarily located in the outer mitochondrial membrane. In prokaryotes, it is found in the cell membrane. A broad spectrum of functions has been attributed to the TSPO, including various host defense responses, developmental processes, and mitochondrial functions. In the present review, we focus on the role of TSPO in immunological responses, apoptosis, and steroidogenesis, to determine whether these functions may be governed by a common denominator including TSPO. At physiological concentrations (nM range), the TSPO specific ligands, PK 11195 and Ro5-4864, appear to be anti-apoptotic. Knockdown of TSPO by genetic manipulation, resulting a reduction by more than 50% in [(3)H]PK 11195 binding, was reported to show anti-apoptotic effects, suggesting a potential pro-apoptotic function of TSPO. However, a reduction of more than 70% of TSPO abundance was found to cause cell death, possibly due to impairment of other essential cell functions. The pro-apoptotic function of TSPO may involve the modulation of the channel formed by the mitochondrial voltage-dependent anion channel (VDAC) and the adenine nucleotide transporter (ANT) [i.e., the mitochondrial permeability transition pore (MPTP)]. The frequently reported pro-apoptotic effects of PK 11195 and Ro5-4864 may be due to sites with low-affinity binding for these specific TSPO ligands, and not directly related to VDAC and ANT. Also at concentrations in the nM range, PK 11195 and Ro5-4864 appear to stimulate steroidogenesis. For this function TSPO by itself appears to suffice i.e. no involvement of VDAC and ANT. TSPO appears to operate as a translocator/channel to transfer cholesterol into mitochondria where it is converted to pregnenolone, a precursor of further steroidogenesis. Apoptosis and steroids play important roles in various aspects of the host defense response. Thus, our review suggests that the involvement of TSPO and its ligands in such seemingly disparate biological functions as immunological responses, apoptosis, and steroidogenesis may have a common denominator in the multi-dimensional role of TSPO in the host-defense response to disease and injury.

The 18 kDa Translocator Protein and Atherosclerosis in Mice Lacking Apolipoprotein E

“…Thesis, Technion -Israel Institute of Technology, 2008), even though effects in the cardiovascular system can be observed (Dimitrova-Shumkovska et al, 2010a). As has been reported, TSPO levels can be regulated by steroid hormones, which may be part of an organism's response to stress and injury (Anholt et al, 1985;Weizman et al, 1992;Gavish & Weizman, 1997;Gavish et al, 1999;Veenman et al, 2007;Mazurika et al, 2009;. This suggests that TSPO levels may be part of a feedback control system for steroid production (responding to alterations in steroid levels), rather than be regulated by a feed forward signal provided by cholesterol (i.e.…”

“…Various studies over the course of the last 3 decennia have indicated that mitochondrial TSPO, potentially in relation to cardiovascular disease, is involved in the regulation of cholesterol transport into mitochondria in relation to bile production and steroidogenesis (Krueger and Papadopoulos, 1990;Papadopoulos et al, 2006). In particular, TSPO regulates cholesterol transport from the outer to the inner mitochondrial membrane which is the rate-limiting step in steroid and bile acid biosyntheses (Krueger and Papadopoulos, 1990;Lacapère and Papadopoulos, 2003;Veenman et al, 2007). Three-dimensional models of the channel formed by the five α-helices of the TSPO indicate that it can accommodate a cholesterol molecule in the space delineated by the five helices.…”

“…Three-dimensional models of the channel formed by the five α-helices of the TSPO indicate that it can accommodate a cholesterol molecule in the space delineated by the five helices. According to these models, the inner surface of the channel formed by the TSPO molecule would present a hydrophilic but uncharged pathway, allowing amphiphilic cholesterol molecules to cross the outer mitochondrial membrane (Papadopoulos et al, 1997(Papadopoulos et al, , 2006Veenman et al, 2007). At cellular levels TSPO is present in virtually all of the cells of the cardiovascular system, where they appear to take part in the responses to various challenges that an organism and its cardiovascular system face (Veenman & Gavish, 2006), including atherosclerosis and accompanying symptoms (Onyimba et al, 2011;Bird et al, 2010;Dimitrova-Shumkovska et al, 2010a,b,c, 2012.…”

“…Steroid hormones can affect TSPO levels, while in turn TSPO provides a modulatory function for steroid hormone production by regulation of mitochondrial cholesterol transport (Veenman et al, 2007). It is known that cholesterol affects TSPO function (Falchi et al, 2007).…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…[142][143][144] SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b]indole-1-acetamide) is a novel specific and potent TSPO ligand improving functional recovery in rat models of peripheral neuropathy. 145,146 SSR180575 increased pregnenolone accumulation in the brain and sciatic nerve (100% increase at 3 mg/kg, i.p.…”