# Structural Determinants of PIP2 Regulation

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2020 · $773,265

## Abstract

Kir3 or GIRK (G protein gated inwardly rectifying K+) channels are activated by the vagus nerve to control heart
rate. They are critical determinants of heart rate variability (HRV), an index of cardiac health, endowing the heart
with the adaptability it needs to make rapid adjustments in heart rate. GIRK channels are attractive drug targets
against atrial fibrillation (AF), the most common arrhythmia whose prevalence increases with age with an
increased risk of mortality, stroke and myocardial infarction. The lack of specificity of the current antiarrhythmics
used poses significant risk for ventricular side effects. This makes rather attractive targets expressed
predominantly in the atria. Overactivity of cardiac GIRK channels has been implicated under the oxidative stress
conditions characteristic of aging through a dysregulation of Protein Kinase C (PKC) enzymes, such as the
increase in activity of the novel PKCe. Yet, even though full inhibitors of GIRK activity could reverse AF, they
would also inhibit HRV, a side effect detrimental to cardiac health. Thus, the need for specific partial inhibitors
that reverse the PKC-mediated channel activation but do not inhibit the vital functions of the channel is an unmet
medical need. In this proposal, we investigate the mechanism by which PKC-dependent phosphorylation affects
activity and show that it allosterically affects the interactions of the channel with PIP2, the master regulator of
membrane protein function. We identify one phosphorylation site used by PKCe to stimulate channel activity
and propose to determine all the sites involved and identify the gates they allosterically couple with to cause
channel activation. In parallel, we have developed powerful structural computational models that allow us to test
the action of small molecule inhibitors, which also allosterically control distinct channel gates via PIP2. In this
proposal, we aim to set the stage in coupling the molecular insights of small molecule regulators of activity to
specifically reverse the PKC-mediated overstimulation of channel activity. Our small molecule inhibitors will be
tested in transgenic models of PKC-mediated AF with the goal to dial down the aberrant activity enough to correct
the AF problem without compromising cardiac health.

## Key facts

- **NIH application ID:** 10058701
- **Project number:** 2R01HL059949-23
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Diomedes E. Logothetis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $773,265
- **Award type:** 2
- **Project period:** 1998-04-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058701

## Citation

> US National Institutes of Health, RePORTER application 10058701, Structural Determinants of PIP2 Regulation (2R01HL059949-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10058701. Licensed CC0.

---

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