Expression, localization, and functional properties of inwardly rectifying K⁺channels in the kidney

Abstract

Inwardly rectifying K+ (Kir) channels are expressed in multiple organs and cell types and play critical roles in cellular function. Most notably, Kir channels are major determinants of the resting membrane potential and K+ homeostasis. The renal outer medullary K+ channel (Kir1.1) was the first renal Kir channel identified and cloned in the kidney over two decades ago. Since then, several additional members, including classical and ATP-regulated Kir family classes, have been identified to be expressed in the kidney and to contribute to renal ion transport. Although the ATP-regulated Kir channel class remains the most well known due to severe pathological phenotypes associated with their mutations, progress is being made in defining the properties, localization, and physiological functions of other renal Kir channels, including those localized to the basolateral epithelium. This review is primarily focused on the current knowledge of the expression and localization of renal Kir channels but will also briefly describe their proposed functions in the kidney.

Role of collecting duct principal cell NOS1β in sodium and potassium homeostasis

“…A possible explanation for this is that depolarization in the principal cells of these mice stimulates intracellular signaling cascades that stimulate ENaC‐dependent K + secretion (Sorensen et al, 2019 ). This is similar to the concept that K ir 4.1/K ir 5.1 serves as a potassium sensor in the DCT to regulate Na + reabsorption through the sodium chloride cotransporter (Manis et al, 2020 ; Su et al, 2019 ) explaining hypokalemia observed in rodents and humans lacking functional K ir 4.1/K ir 5.1 channels (Celmina et al, 2019 ; Cuevas et al, 2017 ; Malik et al, 2018 ; Palygin, Levchenko, et al, 2017 ; Schlingmann et al, 2021 ; Su et al, 2019 ; Tomilin et al, 2018 ). Thus, the precise effects of changes in K ir 4.1/K ir 5.1 activity on K + homeostasis likely depend on the degree of change as well as the affected nephron segment.…”

“…On the apical membrane, sodium reabsorption through ENaC generates a lumen‐negative transepithelial potential that also drives K + secretion through the ROMK (K ir 1.1) and the big conductance K + (BK) channels (Bailey et al, 2006 ; Wang & Giebisch, 2009 ; Welling, 2016 ). On the basolateral membrane, K + recycling occurs through the basolateral homo‐ and heteromeric K ir 4.1 and K ir 4.1/K ir 5.1 channels (Manis et al, 2020 ; Su et al, 2019 ). Recent preclinical studies have shown that the basolateral K ir 4.1/K ir 5.1 channel is critical for renal salt handling and blood pressure control (Cuevas et al, 2017 ; Palygin, Levchenko, et al, 2017 ; Palygin et al, 2017 ; Penton et al, 2020 ; Tomilin et al, 2018 ; Wang, Su, et al, 2018 ).…”

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies

“…Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the function of the central nervous system, heart, kidney, and other organs [ 5 – 8 ]. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels has been greatly appreciated [ 2 , 5 , 6 ], GOF missense variants in K + channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized [ 9 ].…”

Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat

“…SS Kcnj16-/rats also showed deficits in acute (CNS-respiratory) and chronic (renal) acid/base dysregulation (20). These findings suggest that Kir5.1 plays a non-redundant role in fundamental physiological homeostasis (18,19,(21)(22)(23). Given that Kir5.1 is highly expressed in the CNS, loss of Kir5.1 expression may destabilize the resting membrane potential, thereby altering neuronal excitability and resulting in additional neurological phenotypes.…”