# Comprehensive mapping of trafficking and functional robustness in Inward Rectifier K+ channels for variant pathogenicity prediction and model-guided engineering of chemogenetic reagents

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $316,575

## Abstract

Project Summary
Inward Rectifier K+ channels (KIR) play key roles in the operation of cells in neuromuscular and other tissue.
Pathogenic variants are linked to numerous neurological, cardiovascular, and metabolic disorders. Although
some variants cause gating defects in KIR by altering ligand regulation or ion permeation, there is growing
evidence that many –perhaps most– variants cause defects in folding and trafficking of KIR. Despite the central
role for folding and trafficking in the disease etiology, there have been to date no comprehensive large-scale
studies that determine sequence and structural determinants of KIR trafficking and functional robustness. Here
we provide the first comprehensive assessment of missense and topological mutations’ effects on KIR trafficking
and function. Acquisition of these data is the required first step to build quantitative biophysical model of the
sequence, structure, and function relationship in KIR. These models will be useful to understand the mechanistic
basis for KIR mutation phenotypes, to predict their pathogenicity, and to identify new treatment strategies for KIR-
linked disorders. These models will also pave the way for rational engineering of KIR as chemogenetic reagents
that can be used to study functional roles of K+ channels in intact tissues.

## Key facts

- **NIH application ID:** 10450046
- **Project number:** 5R01GM136851-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Daniel Schmidt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $316,575
- **Award type:** 5
- **Project period:** 2021-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450046

## Citation

> US National Institutes of Health, RePORTER application 10450046, Comprehensive mapping of trafficking and functional robustness in Inward Rectifier K+ channels for variant pathogenicity prediction and model-guided engineering of chemogenetic reagents (5R01GM136851-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10450046. Licensed CC0.

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