Role and mechanisms of regulation of the basolateral Kir4.1/Kir5.1K+ channels in the distal tubules

Epithelial K⁺ channels are essential for maintaining electrolyte and fluid homeostasis in the kidney. It is recognized that basolateral inward‐rectifying K⁺ (K_ir) channels play an important role in the control of resting membrane potential and transepithelial voltage, thereby modulating water and electrolyte transport in the distal part of nephron and collecting duct. Monomeric K_ir4.1 (encoded by Kcnj10 gene) and heteromeric K_ir4.1/K_ir5.1 (K_ir4.1 together with K_ir5.1 (Kcnj16)) channels are abundantly expressed at the basolateral membranes of the distal convoluted tubule and the cortical collecting duct cells. Loss‐of‐function mutations in KCNJ10 cause EAST/SeSAME tubulopathy in humans associated with salt wasting, hypomagnesaemia, metabolic alkalosis and hypokalaemia. In contrast, mice lacking K_ir5.1 have severe renal phenotype that, apart from hypokalaemia, is the opposite of the phenotype seen in EAST/SeSAME syndrome. Experimental advances using genetic animal models provided critical insights into the physiological role of these channels in electrolyte homeostasis and the control of kidney function. Here, we discuss current knowledge about K⁺ channels at the basolateral membrane of the distal tubules with specific focus on the homomeric K_ir4.1 and heteromeric K_ir4.1/K_ir5.1 channels. Recently identified molecular mechanisms regulating expression and activity of these channels, such as cell acidification, dopamine, insulin and insulin‐like growth factor‐1, Src family protein tyrosine kinases, as well as the role of these channels in NCC‐mediated transport in the distal convoluted tubules, are also described.