# Lipid regulation of Cardiac Excitation-Contraction coupling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $602,319

## Abstract

Project Summary
 Experiments outlined in this application, suggest a novel paradigm, that acute angiotensin II (AngII)-stimulated
PIP2 hydrolysis triggers cardiac CaV1.2 channel internalization, providing a means to rapidly tune cellular
excitability and modulate EC-coupling in health. In contrast, we propose that sustained deficits in plasma
membrane CaV1.2 expression, and PIP2 depletion during chronic AngII can trigger a maladaptive compensatory
sympathetic response that improves cardiac function in the short-term but ultimately leads to progressive,
pathological cardiac remodeling, hypertrophy, and potentially arrhythmogenic Ca2+ signaling dysregulation. We
provide compelling preliminary data indicating that PIP2 hydrolysis, downstream of acute AngII/AT1R/Gq
activation, leads to endocytosis of cardiac CaV1.2 channels. We can visualize this endocytosis occurring
dynamically in live ventricular myocytes upon perfusion with physiological concentrations of AngII (100 nM).
Initial results indicate a shift in the balance between channel insertion and removal, such that AngII-stimulated
removal of PM channels, leads to an ~30 % reduction in PM CaV1.2 abundance. We observe a strikingly similar
%-reduction in three other separate experimental approaches, finding decreased ICa in electrophysiology studies,
reduced channel cluster area and expression in super-resolution imaging, and a loss of PM CaV1.2 in surface
biotinylation. We isolate PIP2 as the critical executor of this response, distinct from the activation of PKC and
arachidonic acid production that accompanies AT1R stimulation with experiments that bypass the receptors and
instead utilize a rapamycin-stimulated dimerization system to recruit a 4’,5’ phosphatase to the membrane and
deplete PIP2. Our results support a novel mechanistic role of PIP2 on Cav1.2 channel trafficking and expression
which can be tuned in response to physiological signaling cascades to modulate EC-coupling during acute
regulation of blood pressure. We further propose that chronic depletion of PIP2 during AngII/AT1R signaling
associated with heart failure causes: (i) sustained destabilization of PM CaV1.2 and long-lived expression deficits;
(ii) a compensatory sympathetic response to boost cardiac function involving activation of PKA and CaMKII that
acts in combination with direct AT1R-stimulated CaMKII to enhance CaV1.2 and RyR2 phosphorylation,
producing enhanced Po and diastolic leak that stimulates CaN/NFAT and hypertrophic gene expression; (iii)
enhanced IP3 production that also stimulates CaN/NFAT and hypertrophic gene expression, and (iv) cytoskeletal
instability as a result of depletion of cardioprotective PI(3,4,5)P3 and enhanced ROS-induced microtubule
catastrophe that disrupts channel delivery and promotes biomechanical instability, t-tubule and loss of dyads.
We propose to rigorously test these ideas in two specific aims described herein.

## Key facts

- **NIH application ID:** 10451117
- **Project number:** 1R01HL159304-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Rose Ellen Dixon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $602,319
- **Award type:** 1
- **Project period:** 2022-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451117

## Citation

> US National Institutes of Health, RePORTER application 10451117, Lipid regulation of Cardiac Excitation-Contraction coupling (1R01HL159304-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10451117. Licensed CC0.

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