Altered peripheral benzodiazepine receptor binding in cardiac and liver tissues from thyroidectomized rats

doi:10.1016/0024-3205(94)00523-0

Life Sciences

Volume 55, Issue 24, 1994, Pages 1911-1918

https://doi.org/10.1016/0024-3205(94)00523-0 Get rights and content

Abstract

We measured the density and affinity of the peripheral benzodiazepine receptor (PBR) ligand, [³H]4′-Cl-diazepam, in cardiac ventricular and liver homogenates from thyroidectomized (TX) Holtzman adult male rats, and compared these data to sham-operated controls. When data from hypothyroid tissues were compared to those of controls, the densities of PBRs were decreased in cardiac ventricles but not in liver tissue. This reduction in cardiac PBR density is opposite to what has been reported for ventricular calcium channel density in hypothyroidism. PBR affinity for the ligand was increased in both the liver and ventricular homogenates from the hypothyroid tissues, but this difference was not seen in membranes prepared from the liver homogenates. Although 4′-Cl-diazepam affinity is reported to vary between tissues from different species, this is the first report of an in vivo hormone treatment induced change in the benzodiazepine type PBR affinity. Liver tissues from both groups failed to show any interaction when radiolabeled [³H]4′-Cl-diazepam was tested against competing concentrations of thyroid hormone analogs.

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Mitochondrial translocator protein (TSPO): From physiology to cardioprotection
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A summary of the data tends to indicate that repeated stress induces a down-regulation of the protein whereas an acute stress would promote up-regulation. Indeed, it has been reported that thyroïdectomy [74], inescapable tail shocs [75,76] and noise exposure [77] reduced the density of TSPO in rat heart. This was also observed in a fearful strain of rats [78].
The mitochondrial translocator protein (TSPO) is a high affinity cholesterol binding protein which is primarily located in the outer mitochondrial membrane where it has been shown to interact with proteins implicated in mitochondrial permeability transition pore (mPTP) formation. TSPO is found in different species and is expressed at high levels in tissues that synthesize steroids but is also present in other peripheral tissues especially in the heart. TSPO has been involved in the import of cholesterol into mitochondria, a key step in steroidogenesis. This constitutes the main established function of the protein which was recently challenged by genetic studies. TSPO has also been associated directly or indirectly with a wide range of cellular functions such as apoptosis, cell proliferation, differentiation, regulation of mitochondrial function or porphyrin transport.
In the heart the role of TSPO remains undefined but a growing body of evidence suggests that TSPO plays a critical role in regulating physiological cardiac function and that TSPO ligands may represent interesting drugs to protect the heart under pathological conditions.
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Citation Excerpt :
These ligands have been extensively investigated for their cellular effects on mBzR in the heart.12,16,17 In thyroidectomized Holtzman adult male rats, it has been shown that the mBzR binding sites with exogenous ligand (4′-Cl-DZP) from cardiac ventricular homogenate were decreased, whereas its affinity was increased.18 However, in the heart of male mice after copulation, cardiac mBzR binding sites were increased and its affinity was not altered.19
Mitochondrial benzodiazepine receptor (mBzR) is a type of peripheral benzodiazepine receptor that is located in the outer membrane of mitochondria. It is an 18-kDa protein that can form a multimeric complex with voltage-dependent anion channel (32 kDa) and adenine nucleotide translocator (30 kDa). mBzR is found in various species and abundantly distributed in peripheral tissues, including the cardiovascular system. The mitochondria are well known as the site of energy production, and the heart is the organ that highly requires this energy supply. In the past decades, it has been shown that mBzR plays a critical role in regulating mitochondrial and heart functions. A growing body of evidence demonstrates that mBzR is associated with regulation of mitochondrial respiration, mitochondrial membrane potential, apoptosis, and reactive oxygen species production. Moreover, mBzR has been suggested to play a role in alteration of physiological effects in the heart such as contractility and heart rate. mBzR is involved in the pathologic condition such as ischemia/reperfusion injury, responses to stress, and changes in electrophysiological properties and arrhythmogenesis. In this review, evidence of the roles of mBzR in the heart under both physiological and pathologic conditions is presented. Clinical studies regarding the use of pharmacologic intervention involving mBzR in the heart are also discussed as a possible target for the treatment of electrical and mechanical dysfunction in the heart.
Le récepteur mitochondrial des benzodiazépines (mBzR) est un type de récepteur périphérique des benzodiazépines situé dans la membrane externe de la mitochondrie. C'est une protéine 18 kDa qui peut former un complexe multimérique avec le canal anionique voltage-dépendant (32 kDa) et le translocateur des nucléotides adényliques (30 kDa). Le mBzR se retrouve dans différentes espèces et est abondamment distribué dans les tissus périphériques, incluant le système cardiovasculaire. Les mitochondries sont bien connues comme étant le site de production d'énergie, et le cœur est l'organe qui requiert le plus grand approvisionnement énergétique. Au cours des dernières décennies, il a été démontré que le mBzR joue un rôle critique dans la régulation mitochondriale et les fonctions du cœur. Un nombre croissant de preuves démontrent que le mBzR est associé à la régulation de la respiration mitochondriale, au potentiel de la membrane mitochondriale, à l'apoptose et à la production d'espèces réactives de l'oxygène. De plus, le mBzR semble jouer un rôle dans les modifications physiologiques du cœur comme la contractilité et la fréquence cardiaque. Le mBzR est impliqué dans des pathologies tels les lésions d'ischémie-reperfusion, les réponses au stress, et les changements dans les propriétés électrophysiologiques et l'arythmogenèse. Dans cette revue, les rôles du mBzR sur le cœur sont mis en évidence tant dans des conditions physiologiques que pathologiques. Des études cliniques au sujet de l'utilisation d'interventions pharmacologiques impliquant le mBzR pour le cœur sont aussi discutées comme un objectif possible dans le traitement des dysfonctions électriques et mécaniques du cœur.
The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development
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Peripheral-type benzodiazepine receptors (PBRs) are abundant in the cardiovascular system. In the cardiovascular lumen, PBRs are present in platelets, erythrocytes, lymphocytes, and mononuclear cells. In the walls of the cardiovascular system, PBR can be found in the endothelium, the striated cardiac muscle, the vascular smooth muscles, and the mast cells. The subcellular location of PBR is primarily in mitochondria. The PBR complex includes the isoquinoline binding protein (IBP), voltage-dependent anion channel (VDAC), and adenine nucleotide transporter (ANT). Putative endogenous ligands for PBR include protoporphyrin IX, diazepam binding inhibitor (DBI), triakontatetraneuropeptide (TTN), and phospholipase A2 (PLA2). Classical synthetic ligands for PBR are the isoquinoline 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide (PK 11195) and the benzodiazepine 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5 4864). Novel PBR ligands include N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), both possessing steroidogenic properties, but while FGIN-1-27 is pro-apoptotic, SSR180575 is anti-apoptotic. Putative PBR functions include regulation of steroidogenesis, apoptosis, cell proliferation, the mitochondrial membrane potential, the mitochondrial respiratory chain, voltage-dependent calcium channels, responses to stress, and microglial activation. PBRs in blood vessel walls appear to take part in responses to trauma such as ischemia. The irreversible PBR antagonist, SSR180575, was found to reduce damage correlated with ischemia. Stress, anxiety disorders, and neurological disorders, as well as their treatment, can affect PBR levels in blood cells. PBRs in blood cells appear to play roles in several aspects of the immune response, such as phagocytosis and the secretion of interleukin-2, interleukin-3, and immunoglobulin A (IgA). Thus, alterations in PBR density in blood cells may have immunological consequences in the affected person. In conclusion, PBR in the cardiovascular system may represent a new target for drug development.
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For over 20 years, numerous investigations have focused on elucidating the function of the peripheral benzodiazepine receptor (PBR). This relatively small protein (18 kDa) arouses great interest because of its association with numerous biological functions, including the regulation of cellular proliferation, immunomodulation, porphyrin transport and heme biosynthesis, anion transport, regulation of steroidogenesis and apoptosis. Although the receptor was first identified as a binding site for the benzodiazepine, diazepam, in peripheral organ systems, the PBR was subsequently found to be distinct from the central benzodiazepine receptor (CBR) in terms of its pharmacological profile, structure, subcellular localization, tissue distribution and physiological functions. The PBR is widely expressed throughout the body, with high densities found in steroid-producing tissues. In contrast, its expression in the CNS is restricted to ependymal cells and glia. The benzodiazepine Ro5-4864 and the isoquinoline carboxamide PK11195 exhibit nanomolar affinity for the PBR, and are the archtypic pharmacological tools for characterizing the receptor and its function. Primary among these functions are its regulation of steroidogenesis and apoptosis, which reflect its mitochondrial localization and involvement in oxidative processes. This review will evaluate the basic pharmacology and molecular biology of the PBR, and highlight its role in regulating mitochondrial function, the mitochondrial transmembrane potential and its sensitivity to reactive oxygen species (ROS), and neurosteroid synthesis, processes relevant to the pathogenesis of a number of neurological and neuropsychiatric disorders.
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Both vitamin A and peripheral benzodiazepine receptors (PBRs) are involved in the control of cell proliferation and differentiation. The objective of this study was to determine whether vitamin A deficiency causes any modulation in the binding characteristics of the PBRs. Forty-five weanling guinea pigs were divided into three groups (control, pair-fed control, and vitamin A-deficient). Vitamin A-deficiency status was achieved after 90 days of feeding. It caused atelectasis, hyperplasia and metaplasia of alveolar epithelium, acute inflammation of the tracheobronchial tree, and a significant increase in the number of alveolar type II cells. In comparison to the control and pair-fed control groups, the lung of vitamin A-deficient animals had 40.6 and 42.8% less PBR density, respectively. There was no significant difference in the equilibrium dissociation constant (K_D) of PBRs between the control and the pair-fed control groups, whereas the K_D value was 77.7 and 60% higher in the vitamin A-deficient group than in the control and the pair-fed control groups, respectively. Furthermore, vitamin A deficiency caused a decrease in the binding capacity of PBRs in both nuclear and mitochondrial fractions. These results may suggest a close functional relationship between vitamin A and PBRs.
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Altered peripheral benzodiazepine receptor binding in cardiac and liver tissues from thyroidectomized rats

Abstract

Clin Neuropharmacol

Life Sci

Endocr Rev

Mol Pharmacol

Endocrinology

Mol Endocrinol

Neurochem Res

J Neurochem

J Neurochem

Eur J Pharmacol

J Neurochem

Anal Biochem

Anal Biochem

Anal Biochem