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Rapidly evolving neuroscience has resulted in an exponential expansion in the understanding of benzodiazepine receptors. As a result multiple, potentially confusing nomenclatures have developed.
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The term “central benzodiazepine receptors” is used to refer to benzodiazepine binding sites on GABAergic neurons of the nervous system. Although benzodiazepine binding to the GABAA receptor cannot occur unless at least one γ subunit is present,18 the actual site of benzodiazepine binding is located at the interface of an α and a γ subunit; most commonly an α1 and a γ2 subunit.13,85 Since most receptors only contain a single α subunit, only one benzodiazepine binding site usually exists on each GABAA receptor. Anatomical variations in the α isoforms produce two common patterns of expression that account for some of the clinical variations between benzodiazepines and the pyrazolopyrimidines mentioned earlier. In older nomenclature, benzodiazepine type 1 (BZ1) receptors were also called ω1 receptors. They have a predominance of the α1 isoform, are located in the sensory and motor areas of the brain, and mediate sedative and hypnotic effects. Benzodiazepine type 2 (BZ2) receptors were also called ω2 receptors. They have a predominance of the α2, α3, or α5 isoforms, are located in the subcortical and limbic areas of the brain, and mediate anxiolytic and anticonvulsant effects.57 Most typical benzodiazepines have substantial affinity for the α1, α2, α3, and α5 isoforms, which explains their combined sedative-hypnotic, anxiolytic, and anticonvulsant effects. In contrast, the pyrazolopyrimidines (such as zolpidem) have high affinity for α1, intermediate affinity for α2 and α3, and low affinity for α5 isoforms, which explains their lack of anticonvulsant effect.28,59 The α4 confers resistance to benzodiazepines. This older nomenclature (BZ and ω receptors) is now simplified with GABAA receptors classified as having high, low, or intermediate affinity benzodiazepine binding sites.74
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On the opposite side of the α isoform where the benzodiazepine receptor is located is an α–β interface. This interface holds the location of a binding site for neurosteroids (Fig. A23–2).38 These neurosteroids are potent modulators of GABAA receptor function and are important products of the tryptophan-rich sensory protein receptor (peripheral benzodiazepine receptor) stimulation (see below).
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Peripheral Tryptophan-Rich Sensory Protein
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The term “peripheral benzodiazepine receptor” (PBR) was originally used in the 1970s to define any benzodiazepine binding sites outside of the nervous system.11 Since these PBRs were subsequently identified in most tissues, including the central nervous system, the term is best applied to binding sites not located on GABAergic neurons. Other names for PBRs included BZ3 or ω3 receptors to distinguish them from the “central receptors” described above.47 However, numerous nonbenzodiazepines have high-affinity binding for these receptors, and their structure and function are so dissimilar from GABAA-associated benzodiazepine binding sites that other names such as translocator protein (18 kDa), mitochondrial translocator protein (18 kDa), nuclear translocator protein (18 kDa), were appropriate.68,84,90 The most recent conventions have adopted the term tryptophan-rich sensory protein (TSPO) as this refers to its gene and denotes it as a tryptophan-rich sensory protein.24 Although the term PBR remains attractive, for simplicity and consistency, the current term TSPO will be used in remainder of this discussion.
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The TSPO participates in a heterotrimer structure that is composed of an isoquinoline binding protein, which is the actual receptor (TSPO); a voltage-dependent anion channel (VDAC); and an adenine nucleotide transporter (ANT).68 Although the actual function of each subunit is not well appreciated, the minimal functional unit is the TSPO (18 kDa protein).45 Sequencing of TSPOs demonstrates that they are highly conserved in nature, with DNA from bacteria and fungi having a nearly 50% homology of the isoquinoline binding domain with human DNA.24,27 Homology among mammals exceeds 75%.27 These findings suggest that the PBRs perform a “housekeeping function,” that is, they are involved in a process or processes that are essential for life. In higher life forms, TSPOs can be found primarily in the brain, adrenal glands, heart, and kidney. The TSPO protein and the VDAC span the outer mitochondrial membrane, while the ANT bridges the outer and inner membranes (Fig. A23–3). TSPOs are implicated in cholesterol and protoporphyrin transport required for the synthesis of neurosteroids, heme, and bile salts; ischemia and reperfusion; regulation of calcium channels; mitochondrial respiration; apoptosis; microglial activation; and the immune response.27,68,84 More recently, TSPO ligands have been investigated as potential targets for a variety of disorders including anxiety, cancer, ischemia, and others.15,19,26,41,42,63,64,67,69,75,80,91 It is hypothesized that TSPO has two major roles: opening of the mitochondrial permeability transition pore (MPTP) leading to calcium influx and apoptosis,7,23,26,52 and, as noted above, in synthesis of neurosteroids that modulate GABAA function.67,75
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