The ability of the immunophilin FKBP59-HBI to interact with the 90-kDa heat shock protein is encoded by its tetratricopeptide repeat domain.

A protein of apparent molecular mass of approximately 59 kDa of the FK506-binding protein class (FKBP59) has been found associated with the heat shock protein hsp90 included in nontransformed steroid receptor complexes and termed FKBP59-HBI (HBI for Heat shock protein 90 Binding Immunophilin). Further data analysis has revealed that this immunophilin also belongs to the tetratricopeptide repeat family of proteins. In this work, we describe the hsp90-binding domain of FKBP59-HBI. Density gradient centrifugation, gel filtration, and immunoadsorption analyses failed to demonstrate a stable association between FKBP59-HBI and hsp90 in the rabbit reticulocyte lysate. Using a gel-retardation assay, we provide evidence for a specific ATP-independent interaction between highly purified wild-type rabbit FKBP59-HBI and human hsp90 beta. This interaction was not affected by the immunosuppressants FK506 and rapamycin. Examination of the behavior of several mutants led us to conclude that the tetratricopeptide motifs localized in the C-terminal part of FKBP59-HBI are necessary for hsp90 binding.     

Neurosteroids: Expression of Functional 3β-Hydroxysteroid Dehydrogenase by Rat Sensory Neurons and Schwann Cells

Steroids which are synthesized within the nervous system, such as progesterone, have been termed 'neurosteroids'. Levels of progesterone are much larger in peripheral nerves of rats and mice than in plasma, and persist after removal of the steroidogenic endocrine glands. Schwann cells are a source of progesterone: when isolated from embryonic dorsal root ganglia, they can synthesize progesterone from pregnenolone, the obligate precursor of all steroids. Locally produced progesterone has been shown to play an important role in myelination of peripheral nerve. We show here that sensory neurons from embryonic dorsal root ganglia also express 3β-hydroxysteroid dehydrogenase and can convert [³H]pregnenolone to [³H]progesterone. Moreover, when cultured under different conditions and incubated for 24 h in the presence of 100 nM [³H]pregnenolone, they produce 5–10 times more [³H]progesterone than Schwann cells. The conversion of pregnenolone to progesterone by neurons is further increased by a diffusible factor produced by Schwann cells. Sensory neurons can also metabolize progesterone to 5α-dihydroprogesterone, but unlike Schwann cells, they do not produce 3α,5α-tetrahydroprogesterone, a potent positive allosteric modulator of γ-aminobutyric acid type A receptors. We also show that cells isolated from the adult nervous system still have the capacity to convert [³H]pregnenolone to progesterone and its 5α-reduced metabolites: neurons and Schwann cells purified from dorsal root ganglia of 6 week old male rats show a similar pattern of pregnenolone metabolism to cells isolated from 18 day old embryos. These findings further support the important role of progesterone in the development and regeneration of the peripheral nervous system.     

Cortical perfusion response to an electrical stimulation of the auditory nerve in profoundly deaf patients: study with technetium-99m hexamethylpropylene amine oxime single photon emission tomography.

Brain activation procedures associated with single photon emission tomography (SPET) have recently been developed in healthy controls and diseased patients in order to help in their diagnosis and treatment. We investigated the effects of a promontory test (PT) on the cerebral distribution of technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) in 7 profoundly deaf patients, 6 PT+ and one PT-. The count variation in the temporal lobe was calculated on 6 coronal slices using the ratio (Rstimulation-Rdeprivation)/Rdeprivation where R = counts in the temporal lobe/whole-brain count. A count increase in the temporal lobe was observed in all patients and was higher in all patients with PT+ than in the patient with PT-. The problems of head positioning and resolution of the system were taken into account, and we considered that the maximal count increment was related to the auditory cortex response to the stimulus. Further clinical investigations with high-resolution systems have to be performed in order to validate this presurgery test in cochlear implant assessment.     

Plasma calcitonin and breast tumors

In order to evaluate the frequency of elevated circulating calcitonin in patients with bone metastasis plasma calcitonin level was measured in 32 patients with breast carcinoma with and without bone metastasis. Calcitonin was found in normal ranges in all patients without metastasis. In patients with bone metastasis, 4 had normal level, 2 were found with elevated calcitonin. Our results suggest that elevated calcitonin is related to the presence of bone metastasis but is not a constant finding in these patients.     

Antiprogesterone effect and midcycle (periovulatory) contraception

Based on the sequential changes of hormones in plasma and of progesterone binding sites in the uterus, it is suggested to give once a month, at midcycle (around ovulation), either progesterone itself or a parent compound binding to progesterone receptor. The aim is an antiprogesterone effect occurring presumably through a decrease of receptor functioning ultimately expressed some days later by lack of implantation.     

The hormonal control of adenylate cyclase in rabbit myometrium: in vitro inhibition by adenosine and lack of effect of progesterone

The mechanism by which progesterone modifies uterine smooth muscle cell contraction is still unknown. We investigated the biochemical basis of progesterone effects on myometrium of estradiol-primed rabbits. Progesterone did not affect adenylate cyclase basal activity and displayed no interaction with stimulators of myometrium adenylate cyclase (NaF, guanylyl nucleotides, beta-adrenoreceptor agonists, prostaglandins, forskolin) or with adenosine. On the other hand, adenosine inhibited myometrial adenylate cyclase, which correlates with its contracting properties in vivo; this inhibition is mediated through interaction at 'P sites'. We conclude that whilst adenosine inhibits myometrial adenylate cyclase by acting at 'P sites', progesterone does not interact directly with adenylate cyclase to regulate myometrial contractility.     

Meta-iodobenzylguanidine adrenal medulla localization: Autoradiographic and pharmacologic studies

In order to investigate the mechanism of uptake of meta-iodobenzylguanidine (mIBG) by the adrenal glands, autoradiographic and pharmacologic studies were performed in mice and dogs receiving radioiodinated mIBG.In mice, on macroautoradiography of whole body sections 48 h after¹²⁵I-mIBG, most of the radioactivity was focused in the adrenal glands. On microautoradiography, silver grains were exclusively located in the adrenal medulla.Tissue counting after phenoxybenzamine, cocaine, and desipramine treatment resulted in 45%, 35%, and 0% inhibition of mIBG uptake, respectively. Tissue counting and scintigraphic studies demonstrated a more than 50% mIBG release from the adrenal glands after reserpine.These data indicate the high affinity of mIBG for adrenal medulla and suggest that the mIBG and catecholamine uptake mechanisms are only partially the same.