# Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $381,315

## Abstract

ABSTRACT
Sinoatrial node (SAN) dysfunction (SND) is associated with abnormal impulse formation and propagation in the
SAN. Recent estimates suggest that >75,000 new cases of SND occur in the U.S. every year and that this
number will more than double by 2060. At present, surgical implantation of permanent pacemakers remains the
most efficient treatment of SND which, however, is limited when compared with pharmacologic therapy and costs
$2 billion annually in the U.S. Contemporary evidence suggests an emerging role of compartmentalized
remodeling (i.e. associated with distinct, spatially-confined micro-domains) of pacemaker proteins in SND. Our
studies and others have demonstrated that the proteins involved in pacemaking activity are associated with
specific membrane microdomains, caveolae, i.e., small (50–100 nm) invaginations of the plasma membrane
enriched by cholesterol, sphingolipids and scaffolding proteins caveolin-3 (Cav3). Here, we propose that Cav3
organizes specialized pacemaker signaling complexes providing functional coupling between the sarcolemmal
proteins (referred to as a surface ‘membrane clock’) and subcellular Ca2+ machinery (referred to as an
‘intracellular Ca2+ clock’). We hypothesize that disruption in subcellular targeting of pacemaker proteins and
associated signaling molecules upon structural remodeling of the SAN, may affect their biophysical properties
and neurohormonal regulation as well as protein-protein interactions within the pacemaker signaling complex
disturbing rhythmic generation of action potentials and thus contributing to the pathophysiology of the SND. This
research introduces a novel concept of electrophysiological changes resulting from alternations in the subcellular
compartmentalization of signaling complexes following structural remodeling. This extends beyond the classical
concept of electrical remodeling, according to which dysfunction can be explained by straightforward increases
or decreases in protein expression alone, and adds a new dimension to cardiovascular disease. This research
will open completely new avenues for sophisticated and more effective therapeutic approaches targeted at
preventing the degradation of cardiac cytoarchitecture.

## Key facts

- **NIH application ID:** 10127689
- **Project number:** 5R01HL141214-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Alexey V Glukhov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,315
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127689

## Citation

> US National Institutes of Health, RePORTER application 10127689, Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling (5R01HL141214-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10127689. Licensed CC0.

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