[
Journal of Gerontology,
1988]
Genetic approaches have been used to gain insights into many complex biological phenomena, but until recently most attempts to use genetic approaches to understand aging or senescence processes in metazoans have met with little success. The first review in this series (Martin and Tucker, 1988) surveyed model organisms used in the genetic analysis of aging; here I will review the analysis of life span and of the aging process by means of genetics. Problems inherent in the genetic analysis of aging will be reviewed first. Successful applications of genetics to the phenomena of aging will next be highlighted. Finally, I will present examples of ways in which both molecular and classical genetic approaches can be fruitfully and realistically applied to the study of the aging processes. Where applicable, misinterpretations and possible future directions will be noted.
[
Physiol Rev,
2018]
CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory -subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl<sup>-</sup> channels, whereas ClC-3 through ClC-7 are 2Cl<sup>-</sup>/H<sup>+</sup>-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl<sup>-</sup> channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.