# Allosteric Modulation of HCN Channels

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $432,290

## Abstract

PROJECT SUMMARY
 Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are critical determinants of
membrane potential and excitability in many types of cells throughout the body, including cardiac pacemaker
cells, central and peripheral neurons, many types of sensory cells, and interstitial cells of Cajal in the colon and
bladder. Consistent with this widespread distribution, HCN channels have been identified as potential drug
targets for treatment of a long list of conditions including angina, heart failure, epilepsy, neuropathic pain,
depression, gastrointestinal dysmotility, and neurogenic bladder. However, the single FDA-approved HCN
channel drug (ivabradine) is limited, owing in part to its non-selective block of all four mammalian HCN
channels isoforms and its off-target block of Kv11.1 (hERG), Nav1.5, and Cav1.2 channels. The need for new,
isoform-specific HCN channel activators and inhibitors has been widely recognized but the lack of information
about allosteric and isoform-specific regulation of HCN channels is a roadblock to the development of novel
therapeutics.
 The long-term goals of this project are to identify naturally-occurring, allosteric regulators of HCN channels
and to understand their mechanisms of action. Achieving these goals will advance understanding of the
physiological and molecular functions of HCN channels and aid in the development of new HCN channel
drugs. The current proposal focuses on our exciting discovery of LRMP and IRAG as two novel, isoform-
specific protein interaction partners of HCN4 channels. LRMP and IRAG are homologous ER transmembrane
proteins that have large cytoplasmic domains. Importantly, LRMP and IRAG only modulate the HCN4 isoform.
Moreover, the two proteins have opposing effects on HCN4: LRMP causes a loss-of-function (LOF) by
decreasing the canonical depolarizing shift in voltage-dependence induced by cAMP while IRAG causes gain-
of-function (GOF) by shifting the basal voltage dependence of HCN4 to more positive potentials. Preliminary
data establish that IRAG is co-expressed with HCN4 in cardiac pacemaker cells. Proposed aims will identify
interaction sites on the three proteins, determine the molecular mechanisms for the distinct and isoform-
specific effects, and evaluate their role in pacemaker cells.

## Key facts

- **NIH application ID:** 10367342
- **Project number:** 1R01GM140004-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** CATHERINE PROENZA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,290
- **Award type:** 1
- **Project period:** 2021-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367342

## Citation

> US National Institutes of Health, RePORTER application 10367342, Allosteric Modulation of HCN Channels (1R01GM140004-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10367342. Licensed CC0.

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