Hypertrophy and altered activity of the adrenal cortex in Homer 1 knockout mice.

Homer 1 gene products are involved in synaptic transmission and plasticity, and hence, distinct behavioral abnormalities, including anxiety- and depression-like behaviors, have been observed in Homer 1 knockout (KO) mice. Here we report that Homer 1 KO mice additionally exhibit a pronounced endocrine phenotype, displaying a profoundly increased adrenal gland weight and increased adrenal/body weight ratio. Histological examinations of Homer 1 deficient adrenal glands revealed an increased size of the adrenal cortex, especially the sizes of the zona fasciculata and zona glomerulosa. Moreover, the plasma corticosterone and aldosterone were higher in Homer 1 KO than wild-type (WT) mice while the plasma ACTH levels were not different between the genotypes. The in vivo ACTH test revealed that corticosterone and aldosterone plasma levels were higher in saline injected Homer 1 KO mice than in WT mice (saline injected mice served as controls for the respective groups of ACTH-injected animals), but the magnitude of steroid responses to ACTH was similar in both genotypes. In contrast, an in vitro experiment performed on isolated cells of adrenal cortex clearly showed increased production of both steroids in response to ACTH in Homer 1 KO cells, which is in line with an ~8-fold increase in the expression of ACTH receptor mRNA in the adrenal cortex of these mutants. These results, together with the detection of Homer 1 mRNA and protein in the adrenal cortex of WT mice, indicate that Homer 1 directly affects the steroidogenic function of the adrenal glands.

Complexes of Peptide Blockers with Kv1.6 Pore Domain: Molecular Modeling and Studies with KcsA-Kv1.6 Channel.

Potassium voltage-gated Kv1.6 channel, which is distributed primarily in neurons of central and peripheral nervous systems, is of significant physiological importance. To date, several high-affinity Kv1.6-channel blockers are known, but the lack of selective ones among them hampers the studies of tissue localization and functioning of Kv1.6 channels. Here we present an approach to advanced understanding of interactions of peptide toxin blockers with a Kv1.6 pore. It combines molecular modeling studies and an application of a new bioengineering system based on a KcsA-Kv1.6 hybrid channel for the quantitative fluorescent analysis of blocker-channel interactions. Using this system we demonstrate that peptide toxins agitoxin 2, kaliotoxin1 and OSK1 have similar high affinity to the extracellular vestibule of the K+-conducting pore of Kv1.6, hetlaxin is a low-affinity ligand, whereas margatoxin and scyllatoxin do not bind to Kv1.6 pore. Binding of toxins to Kv1.6 pore has considerable inverse dependence on the ionic strength. Model structures of KcsA-Kv1.6 and Kv1.6 complexes with agitoxin 2, kaliotoxin 1 and OSK1 were obtained using homology modeling and molecular dynamics simulation. Interaction interfaces, which are formed by 15-19 toxin residues and 10 channel residues, are described and compared. Specific sites of Kv1.6 pore recognition are identified for targeting of peptide blockers. Analysis of interactions between agitoxin 2 derivatives with point mutations (S7K, S11G, L19S, R31G) and KcsA-Kv1.6 confirms reliability of the calculated complex structure.

[A new KIAA1245 gene family with or without HERV-K LTRs in their introns]. / Novoe semeistvo genov KIAA1245, razlichaiushchikhsia po prisutstviiu v intronakh LTR HERV-K.

A transcript containing the long terminal repeat (LTR) and the sequence homologous to the KIAA1245 mRNA fragment were revealed among the transcribed LTRs of human endogenous viruses of the K family in normal and tumor tissues. Ten other sequences with a high level of homology to the KIAA1245 mRNA were found in the GenBank. The intron-exon structures were determined for all the sequences, and their exon sequences were compared. The comparison showed that they differ both in the extent of the exon homology and in the presence or absence of the HERV-K LTR in the third intron. The revealed sequences form a new gene family that comprises at least four subfamilies. Two of these subfamilies have the LTR, and the other two do not. We showed by PCR that the LTR was integrated into the introns after the divergence of the orangutan evolutionary branch from other hominoids but before the divergence of the gorilla branch, i.e., 8-13 million years ago. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.

[Study of the quality of life in patients with glaucoma]. / Issledovanie kachestva zhizni u bol'nykh glaukomoi.

The purpose of the study was the assessment of the perception of the disease (glaucoma) and life quality (LQ) by a patient and interrelations between the objective parameters of visual functions and the self-assessment of the condition in patients with glaucoma. A total of 74 glaucoma patients were prospectively examined. The SF-36 russified version and adapted, by the authors, NEI-VFQ-25, 2000, method were made use of. Threshold testing 24-2 and Esterman's binocular screening test were used to detect any disorders in the peripheral vision. The study results are indicative of that the LQ parameters go down in patients with glaucoma according to both the results of the self-assessment of the health condition as a whole (SF = 36), and in relation with glaucoma (NEI-VFQ-25). The LQ parameters of NEI-VFQ-25 of glaucomatous patients are reliably lower as compared to the control group. A moderate statistically significant correlation was used to determine the LQ dependence on the peripheral vision changes virtually in all NEI-VFQ-25 scales. The LQ dependence on a degree of visual functions' disorders was found to be reliable; however, the LQ indices were notably reduced in glaucomatous patients without visual field defects, which was due to a changed psychological status.

Only those genes of the KIAA1245 gene subfamily that contain HERV(K) LTRs in their introns are transcriptionally active.

Insertion of LTRs into some genome locations might seriously affect regulation of the neighboring genes expression. This hypothesis is widely accepted but, however, not confirmed directly. Earlier, we have identified a family of closely related genes highly similar to the KIAA1245 mRNA counterpart. This family included a subfamily of genes some of which contained and the others lacked an LTR in their structure. We compared transcription of several closely related genes of the subfamily differing in the presence or absence of LTRs. Only LTR-containing genes were transcribed in transformed cell lines, tumorous and embryonic human tissues, whereas LTR-lacking genes remained silent. Since the genes were in the same intracellular microenvironment, we suggested that this effect was most probably due to intrinsic cis-characteristics of integrated LTRs and confirmed this by demonstrating high enhancer activity of KIAA1245 LTRs. The expression of the LTR-containing genes in embryonic tissues might suggest their involvement in evolutionary events during primate speciation.