# Molecular mechanisms and regulation of the calcium pump in the heart

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $308,100

## Abstract

Project Summary
 The long-term goal of this project is to elucidate the molecular mechanisms and regulation of the
calcium pump (sarcoplasmic reticulum Ca2+-ATPase, SERCA) in the heart. SERCA clears cytosolic Ca2+ in
cardiomyocytes, thus playing a central role in Ca2+ regulation in the heart. SERCA is regulated by
phospholamban (PLB), a 52-residue phosphorylation-regulated membrane protein that inhibits the activity of
the pump. A key molecular dysfunction in heart failure (HF) involves impaired Ca2+ transport during diastole,
usually associated with insufficient SERCA expression and unaltered PLB levels, thus yielding lower SERCA
activity due to PLB inhibition. Therefore, there is an urgent need for time-resolved, atomistic characterization of
SERCA activation and SERCA-PLB regulation to understand the molecular basis of Ca2+ dysregulation, and to
design appropriate approaches to HF. These mechanisms are complex, requiring structural changes and
interdomain allosteric communication pathways that are difficult to determine experimentally. Since complete
experimental characterization of these changes is likely to remain an intractable problem, we propose to use
molecular simulations as a complementary approach. The central hypothesis of this project is that molecular
simulations at appropriate spatiotemporal scales are uniquely suited to provide a time-resolved detection of
SERCA mechanisms and regulation at a level of resolution currently inaccessible through experiments alone.
The high-resolution mechanistic information from these studies can be directly used for computer-aided
discovery of hits that activate SERCA through specifically targeting the SERCA-PLB interaction. To verify and
consolidate these hypotheses, we have developed a robust battery of computational biophysics and virtual
high-throughput screening approaches to SERCA and SERCA-PLB. Three Specific Aims will be pursued: (1)
Map ligand-induced structural changes associated with SERCA activation. (2) Determine the molecular
mechanisms for PLB regulation of SERCA. (3) Perform a structure-based search of hits that activate SERCA.
For this project, we focus on skeletal SERCA1a because crystal structures have been obtained only for this
isoform, but the structural results from our simulations are directly applicable to cardiac SERCA2a because
there are no significant differences in the kinetics and function of both isoforms, including regulation by PLB.
The simulation work will be closely coupled to experimental studies through collaborations; the combination of
structural and functional data will provide the experimental tests necessary to verify our simulations and refine
our structural models. Activation of SERCA is a widely pursued therapeutic goal in heart failure, and this
project has great potential for pushing important frontiers in our understanding of SERCA function and
regulation, ultimately enabling a more rational approach to address a critical problem in human health.

## Key facts

- **NIH application ID:** 9964846
- **Project number:** 5R01GM120142-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lennane Michel Espinoza-Fonseca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,100
- **Award type:** 5
- **Project period:** 2016-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964846

## Citation

> US National Institutes of Health, RePORTER application 9964846, Molecular mechanisms and regulation of the calcium pump in the heart (5R01GM120142-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964846. Licensed CC0.

---

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