The respiratory system in health and disease : Friday March 1 1996 / The Wellcome Centre for Medical Science.
- Date:
- 1995
Licence: Public Domain Mark
Credit: The respiratory system in health and disease : Friday March 1 1996 / The Wellcome Centre for Medical Science. Source: Wellcome Collection.
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![G-PROTEIN REGULATION OF ALVEOLAR SODIUM CHANNELS; WHY BABIES DON'T DROWN AT BIRTH Gregor KFyfe, Paul] Kemp, Somnath Mukhopadliyay and Richard E Olver Department of Child Health, University of Dundee, Ninewells Hospital and Medical School, Dundee DDI 9SY Postnatally, vectorial lung epithelial ion transport prevents alveolar flooding, but in the fetus, alveolar flooding is part of a physiological process in which an actively secreted liquid provides a template around which the developing airspaces grow. Interference with this dynamic process results in lung malformation. Accumulated evidence from studies on intact lung indicate that alveolar fluid absorption is dependent upon activation of transepithelial Na* transport.' The functional switch from secretion to absorption is initiated at birth by a (32 adrenoceptor-mediated rise in cAMP which activates amiloride-sensitive Na* conductance in the epithelial apical membrane. Inadequate- activation of this mechanism contributes significantly to neonatal respiratory distress. To investigate the roles of the separate components involved in alveolar fluid homeostasis and its regulation at birth, we have developed preparations of isolated alveolar type II (ATI I) cells and purified ATII apical membrane vesicles (AMV) of mature fetal guinea pig lungs. The conclusion that the apical membrane of the ATII cell is the locus of the Na absorptive step of fluid clearance is based on the observations that: 1 excised patches of ATII cells exhibit a low conductance, Na*-selective, amiloride-sensitive channel;3 2 AMV possess an analogous conductive —Na* flux which is blockable by amiloride and phenamil; 3 incorporation of AMV into lipid bilayers results in functional reconstitution of the relevant channel.5 Using patch-clamp and flux measurements we have shown that ATII channels are up-regulated both by co-localized G proteins and arachidonic acid (AA). The modulation by AA is independent of its metabolism, can be mimicked by a range of structurally diverse fatty acids (FA) - both saturated and unsaturated - and is not attenuated by functional inactivation of G proteins suggesting a role for a direct FA/Na channel interaction. However, the system is complicated by the observation that G protein activity is acutely sensitive to unsaturated FA which suggests that there are two overlapping FA-dependent pathways involved in modulation of fetal alveolar Na* transport. The G protein-dependent pathway is possibly the physiologically more important regulatory route since it shows specificity for unsaturated FA; it also represents a novel and additional level of control of signal transduction in the developing lung to that classically described merely in terms of receptor/G protein interactions and may be a negative feedback loop for the FA signal. Interruption of specific G protein cycling, using toxin-dependent ribosylation, has revealed that unsaturated FA exert their effects via pertussis toxin (FTX)-insensitive G proteins. However, the regulation of Na* channels by exogenous GTP analogues has a significant component which is PTX-sensitive. Therefore, these two regulatory pathways (direct G protein versus FA/G protein) are effective via distinct G protein isoforms.](https://iiif.wellcomecollection.org/image/b20456682_0019.jp2/full/800%2C/0/default.jpg)
