Disease relevance of Kcnj1

• The surviving ROMK null mice have normal gross renal morphology with no evidence of significant hydronephrosis, whereas non-surviving null mice exhibit marked hydronephrosis [1].
• ROMK-deficient mice that survived beyond weaning grew to adulthood; however, they had metabolic acidosis, elevated blood concentrations of Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor urinary concentrating ability [2].
• However, the mechanism of renal K(+) wasting and hypokalemia that develop in individuals with ROMK Bartter's syndrome is not apparent given the proposed loss of the collecting duct SK channel [1].
• It is likely that ROMK forms a critical subunit of the 70-pS K channel, accounting for the loss of apical K secretory channel activity in ROMK Bartter syndrome [3].
• Loss-of-function mutations in the K channel, ROMK (Kir1.1; KCNJ1), cause Bartter syndrome, a genetically heterogeneous disorder characterized by severe reduction in salt absorption by the TAL, Na wasting, polyuria, and hypokalemic alkalosis [3].

High impact information on Kcnj1

• By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK [4].
• This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT [4].
• CFTR has been proposed as a regulator of the 30 pS, ATP-sensitive renal K channel (Kir1.1, also known as renal outer medullar K [ROMK]) that is critical for K secretion by cells of the thick ascending limb (TAL) and distal nephron segments responsive to aldosterone [5].
• In contrast, surface expression and macroscopic current density was augmented by a phosphorylation mimic mutation, Kir1.1 S44D [6].
• The Kir1.1 (ROMK) subtypes of inward rectifier K+ channels mediate potassium secretion and regulate sodium chloride reabsorption in the kidney [6].

Biological context of Kcnj1

• To understand better the pathogenesis of type II Bartter's syndrome, we developed a mouse lacking ROMK and examined its phenotype [2].
• ROMK null mice were polyuric and natriuretic with an elevated hematocrit consistent with mild extracellular volume depletion [1].
• At a membrane potential of -60 mV, both IRK and ROMK had single-exponential open-time distributions, with mean open times of 279 +/- 58 ms (n = 4) for IRK1 and 23 +/- 1 ms (n = 7) for ROMK [7].

Anatomical context of Kcnj1

• Removal of the phosphorylation site by point mutation (Kir1.1, S44A) dramatically attenuated the macroscopic current density in Xenopus oocytes [6].
• The expression of ROMK channels in the plasma membrane is regulated by protein tyrosine kinase (PTK), serum and glucorticoid-induced kinase (SGK), and with-no-lysine-kinase 4 [8].
• The decreased surface expression of ROMK caused by mutant WNK4 was postulated to be a mechanism for decreased potassium secretion in distal nephrons that would presumably lead to hyperkalemia [9].
• We show that potassium absorption in the loop of Henle is reduced in Romk-deficient mice and can account for a significant fraction of renal potassium loss [10].

Associations of Kcnj1 with chemical compounds

• Despite loss of ROMK expression, the normokalemic null mice exhibited significantly increased kaliuresis, indicating alternative mechanisms for K(+) absorption/secretion in the nephron [1].
• Increases in superoxide anions induced by low dietary K intake are responsible for the stimulation of PTK expression and tyrosine phosphorylation of ROMK channels [8].
• 1. TNP-ATP binding was specific for the COOH termini of K(ATP) channels because this nucleotide did not bind to the NH(2) termini of Kir1.1 or Kir6 [11].
• Introduction of an arginine at this position in Kir1.1 channels rendered the N-terminal PIP(2) site functional largely increasing the PIP(2) affinity [12].
• Competition of TNP-ATP binding to the Kir1.1 COOH terminus by MgATP was complex with both Mg(2+) and MgATP effects [11].

Other interactions of Kcnj1

• In contrast, Kir1.1 and Kir2.1 channels were insensitive to ethanol and various SSRIs and antipsychotics, although thioridazine weakly inhibited Kir1.1 channels [13].
• Systematic constructions of chimerical Kir6.2-Kir1.1 channels indicated that full pH sensitivity required the N terminus, C terminus, and M2 region [14].
• These currents were insensitive to tolbutemide, a selective blocker of Kir6.x channels, and to tertiapin, a blocker for Kir1.1 and Kir3.1/3.4 channels [15].

Analytical, diagnostic and therapeutic context of Kcnj1

• Western blotting also revealed the presence of the 40 kD ROMK protein using an anti-ROMK antibody [16].
• Here, we used free-flow micropuncture and stationary microperfusion of the late distal tubule to explore the mechanism of renal potassium wasting in the Romk-deficient, Type II Bartter's mouse [10].

References