Cell peripheral benzodiazepine receptor

The third type of benzodiazepine receptor is the so-called peripheral benzodiazepine receptor (pBz). This was first discovered in the rat adrenal gland, hence the term "peripheral". However, it is now known to occur on the platelet membrane, on immune cells and also in the mammalian brain. 

Latham, R S., Verney, E., and Sidransky, H., A high-affinity peripheral benzodiazepine receptor is expressed on nuclei of rat liver cells and a macrophage cell line, Hepatology, 22, 445a, 1995. 

Although tumor cell death is controlled by several mechanisms, one of the dominant mechanisms involves mitochondria [91], It is thus rational to target the mitochondria for therapeutic purposes due to its critical role in the regulation of apoptosis. One potential target is the mitochondrial permeability transition pore (MPTP), the most significant component of which appears to be the peripheral benzodiazepine receptor known as the translocator protein [92]. Various ligands for the translocator protein have shown both anti-proliferative and pro-apoptotic activity or may act as chemo-sensitizers via modulation of MPTP [93-95]. 

Chelli B, Lena A, Vanacore R et al. (2004) Peripheral benzodiazepine receptor ligands mitochondrial transmembrane potential depolarization and apoptosis induction in rat C6 glioma cells. Biochem Pharmacol 68 125-134... 

Figure 3. Schematic architecture of mitochondrial protein complexes. A transmembrane channel, called the permeability transition pore (FTP), is formed at the contaa sites between the inner and outer mitochondrial membrane (OM) of the mitochondria. The core components of PTP are the voltage-dependent anion channel (VDAC) in the outer membrane and the adenine nucleotide translocator (ANT) in the inner membrane (IM). VDAC allows diilusion of small molecules (<5 kDa), however ANT is only permeable to a few selected ions and metabolites and is responsible for maintaining the proton concentration gradient (pH) and the membrane elearic potential (A P,J. PTP is sometimes connected to destruction of permeability barrier and loss of the inner membrane potential and eventually results in mitochondrial membrane permeability transition during apoptosis and other specialized forms of cell death. Bax, Bak, Bc1-Xl and Bcl-2 locate in the outer membrane and may regulate the outer membrane permeability. The translocase of the outer membrane (TOM) and the translocase of the inner membrane (TlM) mediate protein import pathway in the mitochondria. Cy-D, cyclophilin D PBR, peripheral benzodiazepine receptor HK, hexokinase mtHSP70, mitochondrial heat shock protein 70.

Belanger, M., Ahboucha, S., Desjardins, P. and Butterworth, R.F. Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes consequences for neuronal excitability. Adv. Mol. Cell Biol. 31 983-997,2004. 

The binding sites for benzodiazepines are divided into central and peripheral types. The central or neuronal benzodiazepine receptors are influenced by GABA, linked to chloride channel, and responsible for mediating the anxiolytic, sedative, and anticonvulsant properties of the benzodiazepines. The peripheral or nonneuronal benzodiazepine receptors are found in a variety of tissues, including the kidney, heart, lung, liver, adrenal gland, testis, intestinal smooth muscles, mast cells, platelets, several cell lines, and nonneuronal elements in the central nervous system (CNS). 

It should be noted that in addition to the GABA(A)-R benzodiazepine-binding sites or central benzodiazepine Rs (CBZ-Rs) there are peripheral benzodiazepine Rs (PBZ-Rs) associated with the outer membrane of mitochondria in glial cells and cells of peripheral tissue and which are involved in cholesterol transport and hence in regulation of steroid hormone synthesis. The GABA(B)-Rs are metabotropic and coupled via heterotrimeric G proteins to Ca2+ and K+ channels (Chapter 5). The psychotropic GABA breakdown product y-hydroxybutyrate (GHB) also acts via heterodimeric G protein-linked receptors (see Chapter 5). 

Gamier, M., Dimchev, A., Boujrad, N., Price, J., Must, N. and Papadopoulos, V. (1994) In vitro reconstitution of a functional peripheral-type benzodiazepine receptor from mouse Leydig tumor cells. Mol. Pharmacol, 45,201-11. 

Papadopoulos, V., Amri, H., Li, H., Boujrad, N., Vidic, B. and Gamier, M. (1997) Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2G Leydig tumor cell line. /. Biol. Chem., 272, 32129-35. 

Rocca, P., Bellone, G., Benna, P., Bergamasco, B., Ravizza, L., and Ferrero, P., Peripheral-type benzodiazepine receptors and diazepam binding inhibitor-like immunoreactivity distribution in human peripheral blood mononuclear cells, Immunopharmacology, 25, 163, 1993. 

Fisher R, Schmitt M, Bode JG, Haussinger D (2001) Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells. Gastroenterology 120 1212-1226... 

Papadopoulos, V. (1993). Peripheral-type benzodiazepine/diazepam binding inhibitor receptor biological role in steroidogenic cell function. Endocr Rev 14, 222-240. 

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