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

Abstract

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.

Keywords: Abnormal cell growth; Animal models; Cation-Cl− cotransporter; K+-Cl− cotransporter; Red blood cells; Sickle cell anemia; Submitted to Journal of Hematology and Oncology.

Fig. 1

Structure of KCC1 and classification of the CCC family. a Structure. The topology model shown was drawn with the program PLOT by Biff Forbush (Yale University). Branched lines correspond to glycosylation sites, other symbols to residues and colors other than blue, to functional sites of potential importance. b Phylogenetic tree of the CCC family. The phylogram shown was obtained with the programs PhyML v3.1/3.0 aLRT and MUSCLE v3.8.31 [36, 37] using the most abundant human variants. GenBank accession numbers are provided in footnote 1

Fig. 2

Regulation of K⁺-Cl⁻ cotransport in HbS cells. During occlusive crises, PGIF are produced from ischemic non-erythroid tissues and taken up by RTC where it could increase KCC1 expression and overcome the potential inhibitory effect of low pO_2i on K⁺-Cl⁻ cotransport. Abbreviations: HbS, hemoglobin S; HIF, hypoxia-induced factor; PIGF, placental growth factor

Fig. 3

Role of KCC1 in osteoclasts. On the ruffled border, transport systems shown consist of KCC1, the Cl⁻ channel CLC-7 [95], and the vacuolar H⁺-ATPase pump ATP6V1C1 [96]. On the basolateral membrane, they consist of the Na⁺/K⁺-ATPase pump ATPA1B1 [97] and the Cl⁻/HCO₃⁻ exchanger SLC4A2 [98]. On the ruffled border, the role of KCC1 could be to use the K⁺ gradient generated by the Na⁺ pump to provide an accessory route for Cl⁻ secretion in resorptive pits [18]. If, alternatively, KCC1 was localized on the basolateral side, it could then serve two purposes. The first one would be to sustain Cl⁻/HCO₃⁻ exchange by providing the antiporter with a continued supply of Cl⁻ ions. The presence of KCC1 at this location would thus allow secondarily for higher H⁺_i and luminal H⁺ secretion. The second one would be to sustain Na⁺/K⁺-ATPase activity by providing the enzyme with a continued supplied of K⁺ ions. The presence of KCC1 at this location would thus allow secondarily for higher intracellular negativity and luminal Cl⁻ secretion