# Molecular mechanism of Na+ -coupled HCO3- transporters:  transport of CO3= and CO2

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $660,603

## Abstract

− transporters (NCBTs, members of the SLC4 family) play critical roles in transepithelial HCO−3
Na+-coupled HCO3
transport, whole-body pH regulation, and intracellular pH (pHi) regulation. In this Multi-PI R01, the team will
exploit powerful techniques, many developed in their respective laboratories, to elucidate molecular transport
mechanisms of NCBTs, which are especially important in the kidney. These tools include surface pH (pHS)
measurements, out-of-equilibrium (OOE) CO2/HCO3− solutions, macroscopic mathematical modeling (MMM) of
acid-base transport in a single cell, and state-of-the-art molecular dynamics (MD) simulations of interactions
between the substrates and the transport molecule, or of CO2 conduction through the NCBTs. In a
multidisciplinary approach, the team will answer 2 major questions. Aim 1: Do all NCBTs carry some form of
 – ion pair—whereas other SLC4 “HCO3− ” transporters actually carry
 =—arriving or departing as the NaCO3
CO3
HCO3− per se? By monitoring pHS in voltage-clamped oocytes the team will test whether SLC4 family members
 − . They will address the same question in perfused proximal tubules (PTs) from wild-
 = ” vs. HCO3
transport “CO3
 – binding to the KKMIK region
type (WT) and NBCe1-A/D knockout mice. They also test the hypothesis that NaCO3
of TM5 is a rate-limiting step for NBCe1-A transport. Using MD, the team will identify/model outward-facing,
occluded, and inward-facing conformational states of NBCe1, NBCn1 and AE1, and identify potential interaction
sites –, =, −, Cl−,
 for NaCO3 Na+, CO3 HCO3 and and use MMM (3D reaction-diffusion simulations) to assess
physiological data. Finally, in an iterative process, the team will assess single nucleotide polymorphisms (m-
 = ” vs. HCO−3
SNPs) as well as other mutations suggested by MD studies, prioritize them, and evaluate for “CO3
transport using physiological assay, interpret using MD and MMM, and suggest new mutations. Aim 2: Do all
 = ” transport,
NCBTs conduct CO2 whereas other SLC4 transporters do not? Having presumably committed to “CO3
evolution faced the challenge of translocating the second carbon atom, ultimately derived from 2×HCO3−. The
team will use electrophysiological techniques and a novel neutral buoyancy assay (NBA) to ask whether all
NCBTs conduct CO2, whereas other SLC4 members do not. In perfused PTs from WT and NBCe1-A/D knockout
mice, they will ask if NBCe1-A conducts CO2 in PTs. The team will use MD to identify potential CO2 pathways
through NBCe1, NBCn1, and AE1 as a negative control. MMM will assess the physiological data. Finally, in an
iterative process, the team will process m-SNPs and other mutations as outlined in Aim 1, but now for effects on
CO2 conduction. The research will reorganize our thinking of NCBT function, providing valuable insight into the
pathogenesis of proximal renal tubular acidosis (pRTA) and other maladies associated with NBCe1 (e.g.,
migraine, ocular and dental abnormalities, suicidal ideation), other NCBTs (...

## Key facts

- **NIH application ID:** 10398247
- **Project number:** 5R01DK128315-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Walter F Boron
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $660,603
- **Award type:** 5
- **Project period:** 2021-04-27 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10398247

## Citation

> US National Institutes of Health, RePORTER application 10398247, Molecular mechanism of Na+ -coupled HCO3- transporters:  transport of CO3= and CO2 (5R01DK128315-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10398247. Licensed CC0.

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