Enigma of the Peripheral Benzodiazepine Receptor

The featured paper is ‘Enigma of the Peripheral Benzodiazepine Receptor’ by Gavish and colleagues which is freely available here.

In the introduction, the authors note the importance of the central GABA/Benzodiazepine receptor complex and describe the occurence of peripheral benzodiazepine receptors (PBR) which also occur in glial cells in the brain as well as other tissues throughout the body. They also discuss compounds which due to their pharmacological properties are able to distinguish between the receptors and also the process of purification using detergents without interfering with the receptor binding properties.

There is no method section and the authors  state that they will review the literature in the field, going on to cite over 200 references on the subject.

The paper is organised into sections on the molecular identity of the PBR, endogenous PRB ligands, role in cellular respiration, role in the endocrine system/steroid regulation, pathological conditions and the PBR, the role of the PBR in cancer and immune function before finishing with summary and future directions. Such is the breadth of material covered that this could be considered as several reviews in one.

When the authors discuss the molecular identity of the PBR they note that it is present in the human kidney and suggest a relationship with steroidogenic tissues.  They also mention the isoquinolone binding subunit. The isoquinolones are a component of coal tar, having also been implicated in the pathogenesis of Parkinson’s Disease. The authors note that the PBR gene has shown significant conservation across species including bacteria (although their receptors appear to be distinct), contains a cholesterol recognition site and that there is still much work to be done in elucidating the function of the Benzodiazepine receptor at the cellular level.

The section on endogenous ligands for the PBR is intriguing particularly in the discussion of DBI as well as the porphyrins. A metaboolite of DBI (diazepam binding inhibitor) referred to as octadecaneuropeptide (ODN) has an affinity for the benzodiazepine binding site and DBI itself has been found in the human brain and interestingly immunoreactivity for DBI is increased in CSF in dementia with normal pressure hydrocephalus but not in a number of other forms of dementia. There is also evidence to suggest its involvement in intracellular cholesterol transport and steroidogenesis. The action of porphyrins on the PBR as well as their concentration in the adrenals and testes further supports a possible role in steroidogenesis of the PBR.

The possible role of PBR’s in cellular respiration is suggested to be unclear at present. The authors then examine the role of PBR’s in steroidogenesis noting their presence in relevant tissues and also on the external wall of mitochondria. Within the section on pathological conditions there are further subdivision. Thus the authors identify the relationship of platelet PBR levels with anxiety levels prior to an examination, and also in the longer term in soldiers participating in parachuting exercises. The authors suggest a mediating role for steroids in this relationship which is biologically plausible. Decreased PBR density was also identified as being reduced in a study of PTSD whereas the results are equivocal with OCD.  The authors further suggest that PBR’s are downregulated in chronic hyperactivity of the autonomic nervous system. The intriguing role of Carbamazepine in upregulating PBR’s is speculated as perhaps having an association with epilepsy although the authors are cautious.

Various studies are examined and a number of possible or speculative associations are suggested including reduced platelet PBR in Parkinson’s Disease, increased PBR density in temporal lobe, pre and postcentral gyrus in Alzheimer’s Disease (the authors question whether gliosis may play a role), dopaminergic agents and EPSE’s in schizophrenia, increased HPA activity in Alzheimer’s Disease as well as in various types of brain damage.

The authors conclude by suggesting a general housekeeping role for the PBR gene as well as a possible role in cell proliferation.

This is a detailed and thought provoking look at a receptor thats role is perhaps underplayed.

STT3

Disclaimer

The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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