# Regulation of excitability in sinoatrial myocytes

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $527,918

## Abstract

The long term goals of this project are to understand the molecular and biophysical mechanisms for the
regulation of cardiac pacemaking in sinoatrial node myocytes (SAMs) across the gamut of physiological
conditions. SAMs function as cardiac pacemaker cells by firing spontaneous action potentials (APs). As in
other excitable cells, the precise shape of sinoatrial APs reflects the composite activity of the unique
complement of ion channels and transporters on the plasma membrane. AP waveforms are not static; they
vary in response to short- and long-term changes in physiological context. In principle, differences in AP
waveforms should lend insight into the changes in ionic currents that underlie cellular electrophysiological
responses. However, our ability to decode the causal relationships between ionic currents and AP shape
remains an elusive goal in all excitable cells. This gap in understanding is caused by a lack of information
about AP waveforms and currents in different physiological contexts and by difficulties inherent to the study of
interrelated systems using conventional research approaches. The present proposal addresses these general
questions by focusing on the mechanisms by which aging slows cardiac pacemaking. Proposed experiments
follow from work in prior funding periods and new preliminary data which show that aging slows pacemaking in
part by decreasing the spontaneous AP firing rate of SAMs in association with changes in a limited subset of
AP waveform parameters and reductions in the funny current (If) and voltage-gated Ca2+ currents (ICa,L and
ICa,T). They also address the prior observation that age-dependent reductions in pacemaker activity and If in
SAMs can be reversed by high concentrations of exogenous cAMP via a cAMP-mimetic mechanism.
Proposed experiments will use new research tools developed during the current funding period (1) to define
age-dependent changes in the relative contributions of currents active during different phases of the AP in
SAMs, (2) to test the ability of different currents, singly and in combination, to transform the AP phenotype of
young and aged SAMs, and (3) to test the hypothesis that age-dependent reduction in a novel If regulatory
protein is responsible for the hyperpolarizing shift in voltage-dependence and resulting slowing of AP firing rate
in SAMs and heart rate in mice. Results of these studies will experimentally define for the first time causal
links between individual ionic currents and AP waveform parameters in SAMs that are responsible for cardiac
pacemaking in general and will reveal how these mechanisms are changed during normal aging.

## Key facts

- **NIH application ID:** 10120022
- **Project number:** 2R01HL088427-11A1
- **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:** $527,918
- **Award type:** 2
- **Project period:** 2008-01-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120022

## Citation

> US National Institutes of Health, RePORTER application 10120022, Regulation of excitability in sinoatrial myocytes (2R01HL088427-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120022. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*