Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response.
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.
Veenman
Leo
L
Department of Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel.
Papadopoulos
Vassilios
V
Gavish
Moshe
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D004703:Endocrine System / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*
D001570:Benzodiazepinones; C463819:Bzrp protein, mouse; D007546:Isoquinolines; D008024:Ligands; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D013256:Steroids; C499229:TSPO protein, human; C028513:4'-chlorodiazepam; C037850:PK 11195