Physiological roles and molecular mechanisms of K⁺‐Cl⁻ cotransport in the mammalian kidney and cardiovascular system: where are we?

Abstract

In the early 80s, renal microperfusion studies led to the identification of a basolateral K+‐Cl− cotransport mechanism in the proximal tubule, thick ascending limb of Henle and collecting duct. More than ten years later, this mechanism was found to be accounted for by three different K+‐Cl− cotransporters (KCC1, KCC3 and KCC4) that are differentially distributed along the renal epithelium. Two of these isoforms (KCC1 and KCC3) were also found to be expressed in arterial walls, the myocardium and a variety of neurons. Subsequently, valuable insights have been gained into the molecular and physiological properties of the KCCs in both the mammalian kidney and cardiovascular system. There is now robust evidence indicating that KCC4 sustains distal renal acidification and that KCC3 regulates myogenic tone in resistance vessels. However, progress in understanding the functional significance of these transporters has been slow, probably because each of the KCC isoforms is not identically distributed among species and some of them share common subcellular localizations with other KCC isoforms or sizeable conductive Cl− pathways. In addition, the mechanisms underlying the process of K+‐Cl− cotransport are still ill defined. The present review focuses on the knowledge gained regarding the roles and properties of KCCs in renal and cardiovascular tissues.

Molecular characteristics and physiological roles of Na+–K+–Cl− cotransporter 2

“…As it stands, nine CCCs have now been uncovered (Garneau et al, 2017; Garneau, Marcoux et al, 2019; Garneau, Slimani et al, 2019; Marcoux et al, 2017). As shown in Figure 1b, they fall into four phylogenetic clades.…”

“…However, their transport dependence on extracellular [Na + ], [K + ], and [Cl − ] was studied by different research groups and found to be consistent with a one ion‐binding site model for each cation and a two ion‐binding site model for Cl − (Gagnon et al, 2004; Gagnon, Forbush, Caron, & Isenring, 2003; Gimenez & Forbush, 2007; Gimenez, Isenring, & Forbush, 2002). It should be nonetheless remembered that such models were inferred from Hill coefficients and that they thus only provide an estimate of the minimal number of binding sites involved (Garneau et al, 2017; Garneau, Marcoux et al, 2019; Garneau, Slimani et al, 2019; Marcoux et al, 2017).…”

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

“…1): KCC1 belongs to one branch along with the three other KCC, the Na + -dependent CCC belong to another branch and the remaining two CCC (called CCC8 and CCC9) belong to each an independent branch. Overall, KCC1 shares higher identity with KCC3 (~ 75%) than with any of the other CCC [1, 3].…”

“…K + -Cl − cotransporter 1 (KCC1) is a membrane protein that mediates the symport of K + and Cl − ions through the surface of most animal cells [1]. It is also referred to as SLC12A4 based on the Human Genome Organization (HUGO) nomenclature.…”

“…KCC1 also shares moderate levels of homology with three additional proteins that mediate the symport movement of Na + and Cl − in the absence or presence of K + . Along with the four KCC isoforms, these additional proteins are all part of a larger family of proteins that are termed cation-Cl − cotransporters (CCC) in the literature [1–4].…”