# Molecular of ROMK Channel Function

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $723,720

## Abstract

ROMK (Kir 1.1, the product of the KCNJ1 gene) channels in the distal nephron are
exquisitely regulated to adjust renal potassium excretion and maintain potassium balance.
Still, the underlying mechanisms have been a great mystery. Here we overcome this major
conceptual roadblock, building on our recent discoveries of a mechanism we call the
potassium switch. We identified two new elements of the switch pathway that regulate
ROMK: structural remodeling of the connecting tubule (CNT), and a plasma potassium
sensing signaling pathway in the CNT, composed of Kidney Specific (KS)-WNK1, WNK4,
and ERK. To carry these breakthrough observations toward a completely new
understanding of how potassium balance is achieved, we will use a stepwise
multidisciplinary approach, combining molecular genetics, genomics, cellular biology,
innovative imaging, state-of-the-art physiological phenotyping in novel mouse models, and
mathematical modeling to: 1) Rigorously explore the physiology of newly developed
inducible cell-specific ROMK knockout to determine if the regulated expression of ROMK
in DCT2 and CNT controls potassium homeostasis, 2) Investigate the adaptive expansion
of the CNT as a normal homeostatic mechanism that preserves potassium balance in the
face of increased dietary potassium consumption. 3) Test if switch activation of the cell-
fate determinants, Jagged 1-Notch 1/2, are required for proper remodeling of the CNT. 4)
Explore a potassium-sensing signaling pathway that downregulates ROMK in potassium
deficiency via KS-WNK1/WNK4/ERK5 phosphorylation of the clathrin adaptor, ARH,
which targets ROMK for endocytosis. The pathway provides a molecular mechanism to
explain how ROMK channels are regulated in hypokalemia and dietary potassium
deficiency and pathologically misregulated in a human disease of familial hyperkalemia
that is induced by gain-of-function mutations in the kidney-specific WNK1. The studies
should provide novel insights into the molecular basis of renal K+ handling and K+
homeostasis in health and disease while illuminating novel drug targets for the treatment
of common hyperkalemic disorders.

## Key facts

- **NIH application ID:** 10800158
- **Project number:** 2R01DK054231-21A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Paul A Welling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $723,720
- **Award type:** 2
- **Project period:** 1998-08-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800158

## Citation

> US National Institutes of Health, RePORTER application 10800158, Molecular of ROMK Channel Function (2R01DK054231-21A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10800158. Licensed CC0.

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