Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K ⁺ channel (ROMK)

Abstract

The renal outer-medullary K ؉ channel (ROMK; Kir1.1) mediates K ؉ secretion in the renal mammalian nephron that is critical to both sodium and potassium homeostasis. The posttranscriptional expression of ROMK in the plasma membrane of cells is regulated by delivery of protein from endoplasmic reticulum (ER) to the cell surface and by retrieval by dynamin-dependent endocytic mechanisms in clathrin-coated pits. The S44 in the NH 2 terminus of ROMK1 can be phosphorylated by PKA and serum-and glucocorticoid-inducible kinase-1, and this process increases surface expression of functional channels. We present evidence that phosphorylation of S44 modulates channel expression by increasing its cell surface delivery consequent to suppression of a COOH-terminal ER retention signal. This phosphorylation switch of the ER retention signal could provide a pool of mature and properly folded channels for rapid delivery to the plasma membrane. The x-ray crystal structures of inward rectifier K ؉ channels have shown a close apposition of the NH 2 terminus with the distal COOH terminus of the adjacent subunit in the channel homotetramer, which is important to channel gating. Thus, NH 2-terminal phosphorylation modifying a COOH-terminal ER retention signal in ROMK1 could serve as a checkpoint for proper subunit folding critical to channel gating.trafficking ͉ dynamin ͉ brefeldin A

Protein phosphatase 1 modulates the inhibitory effect of With-no-Lysine kinase 4 on ROMK channels

“…SGK1 has been reported to stimulate ROMK channels by facilitating the phosphorylation of ROMK channels at the NH 2 terminus thereby enhancing the export of ROMK channels from the endoplasmic reticulum to the plasma membrane (14,32), an effect that requires the involvement of type II Na/H exchanger regulating factor (35). Moreover, SGK1 also suppresses the effect of WNK4 on ROMK channels through the phosphorylation of WNK4 at Ser 1169 (18) and Ser 1196 (19).…”

Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel function by different mechanisms

“…The failure of the R193P and H251Y to efficiently reach the cell surface is likely to be the result of misfolding. A number of trafficking signals have been identified in ROMK that control channel delivery to (15,25,26) and from (3) the cell surface, but R193P and H251Y are not located near any of them. Instead, structural homology modeling of ROMK (23) predicts that R193 and H251 are deeply buried at separate sites within the cytoplasmic domain and not readily accessible to the solventexposed surface.…”

Distal Convoluted Tubule

“…Specifically, the receptor translocates to the nucleus, where it stimulates the transcription of serum-and glucocorticoidregulated kinase 1 (SGK1). SGK1 then phosphorylates a specific residue located in the cytoplasmic tail of ROMK; this event releases the channel from retention in the endoplasmic reticulum, allowing it to traffic more freely to the apical plasma membrane (82)(83)(84). Thus, through direct effects of SGK1 on ROMK traffic, aldosterone seems to ensure that an adequate number of potassium channels are available to facilitate K 1 secretion in the distal nephron.…”