Navigating the multifaceted intricacies of the Na+-Cl- cotransporter, a highly regulated key effector in the control of hydromineral homeostasis.

The Na+-Cl- cotransporter (NCC; SLC12A3) is a highly regulated integral membrane protein that is known to exist as three splice variants in primates. Its primary role in the kidney is to mediate the cosymport of Na+ and Cl- across the apical membrane of the distal convoluted tubule. Through this role and the involvement of other ion transport systems, NCC allows the systemic circulation to reclaim a fraction of the ultrafiltered Na+, K+, Cl-, and Mg+ loads in exchange for Ca2+ and [Formula: see text]. The physiological relevance of the Na+-Cl- cotransport mechanism in humans is illustrated by several abnormalities that result from NCC inactivation through the administration of thiazides or in the setting of hereditary disorders. The purpose of the present review is to discuss the molecular mechanisms and overall roles of Na+-Cl- cotransport as the main topics of interest. On reading the narrative proposed, one will realize that the knowledge gained in regard to these themes will continue to progress unrelentingly no matter how refined it has now become.

Multiple Facets and Roles of Na+-K+-Cl- Cotransport: Mechanisms and Therapeutic Implications.

The Na+-K+-Cl- cotransporters play key physiological and pathophysiological roles by regulating the membrane potential of many cell types and the movement of fluid across a variety of epithelial or endothelial structures. As such, they should soon become invaluable targets for the treatment of various disorders including pain, epilepsy, brain edema, and hypertension. This review highlights the nature of these roles, the mechanisms at play, and the unresolved issues in the field.

K+-Cl- cotransporter 1 (KCC1): a housekeeping membrane protein that plays key supplemental roles in hematopoietic and cancer cells.

During the 1970s, a Na+-independent, ouabain-insensitive, N-ethylmaleimide-stimulated K+-Cl- cotransport mechanism was identified in red blood cells for the first time and in a variety of cell types afterward. During and just after the mid-1990s, three closely related isoforms were shown to account for this mechanism. They were termed K+-Cl- cotransporter 1 (KCC1), KCC3, and KCC4 according to the nomenclature of Gillen et al. (1996) who had been the first research group to uncover the molecular identity of a KCC, that is, of KCC1 in rabbit kidney. Since then, KCC1 has been found to be the most widely distributed KCC isoform and considered to act as a housekeeping membrane protein. It has perhaps received less attention than the other isoforms for this reason, but as will be discussed in the following review, there is probably more to KCC1 than meets the eye. In particular, the so-called housekeeping gene also appears to play crucial and specific roles in normal as well as pathological hematopoietic and in cancer cells.