Adrenal aldosterone-producing adenomas (APAs) are a main cause for primary aldosteronism leading to arterial hypertension. Physiologically, aldosterone production in the adrenal gland is stimulated by angiotensin II and high extracellular potassium. These stimuli lead to a depolarization of the plasma membrane and, as a consequence, an increase of intracellular Ca(2+). Mutations of the plasma membrane Ca(2+)-ATPase ATP2B3 have been found in APAs with a prevalence of 0.6%-3.1%. Here, we investigated the effects of the APA-associated ATP2B3(Leu425_Val426del) mutation in adrenocortical NCI-H295R and human embryonic kidney (HEK-293) cells. Ca(2+) measurements revealed a higher basal Ca(2+) level in cells expressing the mutant ATP2B3. This rise in intracellular Ca(2+) was even more pronounced under conditions with high extracellular Ca(2+) pointing to an increased Ca(2+) influx associated with the mutated protein. Furthermore, cells with the mutant ATP2B3 appeared to have a reduced capacity to export Ca(2+) suggesting a loss of the physiological pump function. Surprisingly, expression of the mutant ATP2B3 caused a Na(+)-dependent inward current that strongly depolarized the plasma membrane and compromised the cytosolic cation composition. In parallel to these findings, mRNA expression of the cytochrome P450, family 11, subfamily B, polypeptide 2 (aldosterone synthase) was substantially increased and aldosterone production was enhanced in cells overexpressing mutant ATP2B3. In summary, the APA-associated ATP2B3(Leu425_Val426del) mutant promotes aldosterone production by at least 2 different mechanisms: 1) a reduced Ca(2+) export due to the loss of the physiological pump function; and 2) an increased Ca(2+) influx due to opening of depolarization-activated Ca(2+) channels as well as a possible Ca(2+) leak through the mutated pump.
Bristle crabs of the genus Pilumnus (Brachyura: Heterotremata: Pilumnidae) are common inhabitants of European waters. They are easily identifiable as a genus, but with the exception of P. inermis, intrageneric classification turns out to be quite complex. There is no general agreement on the number and distinction of species. Therefore, this genus is well-suited for comparative molecular studies. Specimens of the Pilumnus hirtellus complex, here defined as including Pilumnus hirtellus, P. villosissimus, P. spinifer, P. aestuarii, and an undescribed species, were gathered from throughout the Mediterranean Sea and the eastern Atlantic Ocean. DNA sequence data were obtained from the barcoding region of the cytochrome oxidase 1 mitochondrial gene and used for reconstruction of a phylogenetic tree and a haplotype network. The morphology of the gastric ossicles was compared in the search of separating characters. Our results give evidence for five genetic clusters within the P. hirtellus complex. There is negligible geographic variation within these clusters. Unambiguous mtDNA sequences within morphologically variable local populations argue against possible hybridization. The here encountered evolutionary units are relatively young and possibly allow to study ongoing processes of morphological, genetic, and ecological differentiation, leading to speciation and radiations in the coastal marine environment.
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