The Inward Rectifier K⁺ Channel ROMK (K_ir1.1)

The first of the distinctive family of two transmembrane domain inward rectifier K⁺ channels to be cloned was ROMK1¹, now known as K_ir1.1 (see²). The name of these channels is based on their location; renal outer medullary K⁺ channel (ROMK). These channels are involved in electrolyte processing in the kidney and serve to regulate K⁺ recycling in the thick ascending loop of Henle and mediate K⁺ secretion in the distal nephron (see³). In addition, the channel is expressed in brain mainly in the cortex and hippocampus⁴. There are six known splice variants, products of the same gene designated K_ir1.1a-f (according to the nomenclature suggested in²). Many of the splice variants are differentially expressed along the nephron in the kidney, probably contributing locally to electrolyte processing. One variant, K_ir1.1f is ubiquitously expressed in many tissues including brain, heart and skeletal muscle⁵. Two other families of K_ir channels, K_ir4 and K_ir7, are structurally related to K_ir1.1 proteins and were initially marked as members of the same family. These are K_ir4.1, K_ir4.2 and K_ir7.1, which are widely expressed and have different biophysical properties compared to K_ir1.1 channels^6,7.

The activity of ROMK channels was shown to be modulated by many cytosolic factors including protons, ATP and phosphorylation. These channels also interact with the cystic fibrosis transmembrane regulator (CFTR)⁸ and with the sulfonylurea receptor (SUR2B)⁹, which are both regarded as auxiliary subunits for K⁺ (and other) channels.

Like all inward rectifier K⁺ channels, external Ba²⁺ also blocks ROMK channels. The bee venom peptide, Tertiapin (#STT-250), which is also a general K_ir blocker, effectively blocks ROMK channels¹⁰, and δ-Dendrotoxin (#D-380), which is a blocker of some K_V channels, blocks also ROMK1 channels with Kd of 150 nM¹¹. However, a scorpion toxin, Lq2, specifically and potently inhibits ROMK1 channels¹². The physiological importance of these channels is stressed by the finding that mutations in this gene lead to Bartter’s syndrome, an autosomal recessive disease affecting the kidney (see^3,13).

References

1. Ho, K. et al. (1993) Nature 362, 31.
2. Coetzee, W. A. et al. (1999) Anals N. Y. Acad. Sci. 868, 233.
3. Abraham, M. R. et al. (1999) FASEB J. 13, 1901.
4. Kenna, S. et al. (1994) Brain Res. Mol. Brain Res. 24, 353.
5. Kondo C. et al. (1996) FEBS Lett. 399, 122.
6. Shuck, M. E. et al. (1997) J. Biol. Chem. 272, 586.
7. Döring, F. et al. (1998) J. Neurosci. 18, 8625.
8. Wang, W. et al. (1999) Am. J. Physiol. 277, F826.
9. Dong, K. et al. (2001) J. Biol. Chem. 276, 44347.
10. Jin, W. and Lu, Z. (1999) Biochemistry 38, 14286.
11. Imerdy, J. P. et al. (1998) Biochemistry 37, 14867.
12. Lu, Z. and MacKinnon, R. (1997) Biochemistry 36, 6936.
13. Shieh, C. C. et al. (2000) Pharmacol. Rev. 52, 557.