摘要:

SUMMARY1. Studies of a number of hereditary neurodegenerative diseases, the most common of which is Huntington's disease, have identified the expansion of trinucleotide repeats as a common causative mutation.2. The diseases are caused by expansions of CAG repeats, encoding polyglutamine tracts, within the coding regions of a variety of unrelated genes. The mechanism whereby this specific genetic instability leads to selective neurodegeneration is currently unknown.3. Our current understanding of these polyglutamine expansion neurodenerative diseases is outlined. A potential mechanism is discussed whereby subtle alterations in glutamine, and consequently glutamate levels, may induce chronic excitotoxicity and slow cell death in neuronal populations possessing specific glutamate receptors. The potential role of glutamate receptor‐mediated changes to intracellular calcium levels and energy metabolism in the neurodegenerative pathway is also addresse

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01161.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The cardiorespiratory and renal responses to 3h of normobaric whole‐body hypoxic hypoxia (F1O2= 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls.2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole‐body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant.3. Renal fractional lithium excretion decreased significantly in response to whole‐body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes.4. The data indicate that, in humans, both almitrine and whole‐body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics.5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well‐tolerated, whole‐body hypoxic hypixia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01162.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. We investigated candidate loci for salt‐sensitive high blood pressure (BP) in F2 progeny from crossing Wistar‐Kyoto and stroke‐prone spontaneously hypertensive rats.2. In female F2 progeny, systolic and diastolic BP on the 12th day and the seventh month after salt loading was strongly liked with the D3Mgh12 and D3Mgh6 loci on chromosome 3, respectively.3. These loci were linked with BP only in female F2 progeny, not in males.4. These results indicate that hormonal factors may influence salt sensitivity, particularly with respect to gender differ

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01163.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. A missense mutation leading to reduced ligand affinity in the glucagon receptor (GCG‐R) has been found recently to be five‐fold more common in essential hypertensives than normotensives. The present paper provides additional information on patients that harbour this variant and proposes a possible mechanism by which this may lead to hypertension.2. The seven hypertensives with the mutation were all female, had a later age of onset of the disease and a slightly higher body mass index.3. Glucagon is involved in the regulation of fluid and electrolyte excretion. Mutant GCG‐R results in reduced ligand affinity and cAMP response which, in the kidney, would reduce the normal natriuretic effect of glucagon. This could lead to enhanced fluid reabsorption, expansion of extracellular fluid volume and hypertension via long‐term autoregulation of blood p

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01164.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Cloning and sequencing of cDNA encoding gap junction proteins (connexins) has allowed analysis of tissue‐ and stage‐specific patterns of expression as well as the manipulation of expression of both wild‐type and mutant connexin proteins.2. These studies reveal that the 13 rodent connexins have different biophysical properties, such as unitary conductance and permeability/selectivity, are differentially sensitive to various gating stimuli and couple to one another with variable affinity. Moreover, the physiological roles of gap junction channels are being revealed, as both genetic and epigenetic human diseases are ascribed to aberrant gap junction expression, and as animal models are generated by genetic manipulation.3. This symposium brought together physiological insights achieved through the use of molecular techniques, resulting in novel appreciation of the roles of gap junction channels in normal and pathological tissue fun

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01165.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The gating and permselective properties of gap junction channels are important parameters to determine in delineating their role in co‐ordinated tissue function. This is of particular relevance in non‐excitable tissues.2. In the present study gating characteristics of rCx43 are demonstrated. The mean open times are of the order of 0.45‐1.1 s. These values are extraordinarily large.3. The permselectivity of a variety of gap junction channels is also illustrated to show the poor selectivity properties of gap junctions and, hence, their potential to allow the permeation of second messenger molecules.4. Gating and permselectivity, along with diffusion modelling, produce a picture for gap junction channels that is consistent with physiologically relevant modulation or regulation of gap junction channel pa

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01166.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. In the formation and function of gap junction channels two types of gates ought to be discriminated: the docking gate and the channel gates proper. The docking gate is involved in the transformation of a closed hemichannel to a patent gap junction channel. By definition the trigger mechanism for this gate and maybe even the gate itself is contained within the extracellular loops of the gap junction proteins, the connexins. The channel gates proper determine the open and closed states of the complete gap junction channels.2. Probing the docking gate by mutagenesis of connexins and by synthetic peptides indicates that this gate is the consequence of complex interactions between a large fraction of the amino acids comprising the extracellular loops. Probably both inter‐ and intra‐molecular interactions are involved, and disulfide exchange may be entailed in the stabilization of the open and closed states.3. Of the various effectors on the channel gate(s) the voltage effects have obtained the most scrutiny to date. The response of gap junction channels and hemichannels is diverse, the various channels respond differently to transjunctional and membrane potential. No equivalent to the S4 segment representing the voltage sensor in other voltage dependent ion channels is present in the connexin sequences, instead mutations in various segments of connexins have been reported to affect the voltage dependence of gap junction channels. To understand the complexity of voltage effects on gap junction channels, non‐connexin peptides may need to be considered as voltage sensors or as modifiers th

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01167.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Gap junctions and junction‐mediated cell‐to‐cell communications are obligatory features of gland cells, whatever their secretory product is.2. Studies on pancreatic islets and acinar cells indicate that cell‐to‐cell communication via gap junction channels is required for proper biosynthesis, storage and release of both insulin and amylase.3. However, the endocrine and exocrine portions of the pancreas show opposite connexin (Cx) and coupling changes in relation to the activation and inhibition of their secretory functions.4. These differences may be accounted for by the expression of Cx43 in pancreatic islets and of Cx26 and Cx32 in pancreatic acini. This alternative expression of connexin isoforms is also found in several other endocrine and exocrine glands.5. These observations indicate that connexin‐made channels play a central role in the control of secre

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01168.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Trophoblast invasion during embryo implantation in some aspects resembles tumour cell invasion but, unlike tumour cells, trophoblast cells are able to differentiate and establish a placenta. Because direct cell‐cell communication is believed to be involved in growth control and differentiation, we have investigated connexin (cx) gene expression during trophoblast development.2. he‐implantation embryos expressed cx43 as well as ex31 proteins from the 8‐cell stage onwards. Following implantation, compartmentalization of both connexins occurred: cx31 expression was restricted to the invasive trophoblast cell population, whereas the embryo proper was characterized by cx43. Trophoblast differentiation was indicated by induction of cx26 in the labyrinth and cx43 in the spongiotrophoblast accompanied by a disappearance of cx31. Comparison with trophoblast cell lines revealed that rat trophoblast HRP‐1 cells express connexin43, while malignant choriocarcinoma cells express cx31. Treatment with retinoic acid led to a disappearance of cx31 in the choriocarcinoma. Both cell lines reduced their invasion properties after retinoic acid treatment, but growth retardation was only observed in the malignant trophoblast.3. It seems that the cx31 channel is needed for trophoblast cell populations to maintain the highly proliferative properties but does not alter their invasion pro

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01169.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The physiological significance of communication through gap junction channels has been difficult to assess because channel activity cannot be experimentally modulated in a specific manner. To address this problem we have constructed chimeric connexins that function as dominant‐negative inhibitors of intercellular channel activit

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01170.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY