Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease.

The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na+ ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na+ in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension.

In the pathways of steroid hormone biosynthesis there are two major types of enzymes: cytochromes P450 and other steroid oxidoreductases. This review presents an overview of the function and expression of both types of enzymes with emphasis on steroidogenic P450s. The final part of the review on regulation of steroidogenesis includes a description of the normal physiological fluctuations in the steroid output of adrenal cortex and gonads, and provides an analysis of the relative role of enzyme levels in the determination of these fluctuations. The repertoire of enzymes expressed in a steroidogenic cell matches the cell's capacity for the biosynthesis of specific steroids. Thus, steroidogenic capacity is regulated mainly by tissue and cell specific expression of enzymes, and not by selective activation or inhibition of enzymes from a larger repertoire. The quantitative capacity of steroidogenic cells for the biosynthesis of specific steroids is determined by the levels of steroidogenic enzymes. The major physiological variations in enzyme levels, are generally associated with parallel changes in gene expression. The level of expression of each steroidogenic enzyme varies in three characteristics: (a) tissue- and cell-specific expression, determined during tissue and cell differentiation; (b) basal expression, in the absence of trophic hormonal stimulation; and (c) hormonal signal regulated expression. Each of these three types of expression probably represent the functioning of distinct gene regulatory elements. In adult steroidogenic tissues, the levels of most of the cell- and tissue-specific steroidogenic enzymes depend mainly on trophic hormonal stimulation mediated by a complex network of signal transduction systems.

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.