# Understanding and Manipulating Phospholipase C and G Protein beta gamma subunit Signaling Networks

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $592,803

## Abstract

Abstract
G protein-coupled receptors (GPCRs) mediate the actions of a wide variety of hormones and neurotransmitters
to control functions in all mammalian cells. As such, GPCRs are major targets of therapeutics. Individual
GPCRs directly couple to distinct complements of heterotrimeric G protein  and  subunits that drive
downstream signaling pathways to shape the cellular responses that determine GPCR efficacy. Both G and
G subunits interact directly with effectors to produce cellular responses. Our laboratory has focused largely
on G subunit signaling and Phospholipase C (PLC) signaling on projects ranging from analysis of basic
biochemical reaction mechanisms to identification of roles in disease. In this proposal we seek to combine all
of the funded laboratory directions into one proposal. Project 1. We were recently the first to demonstrate that
phosphatidylinositol 4-phosphate is a substrate for PLC activity in cells. This initial study was performed in
cardiac cells. This project is concerned with generalizing this reaction to multiple cell types with the evidence
suggesting that PI4P is a major substrate for receptor stimulated PLC signaling. This has the potential to alter
the paradigm for receptor-dependent regulation of phosphoinositide hydrolysis. Project 2. This project is to
define roles for PLC signaling in the development of heart failure. We have shown the PLC deletion prevents
development of hypertrophy in vitro and in mice. Here we are focused on identifying the mechanistic roles for
PLC signaling in cardiac cells that regulate heart failure. Project 3. We have pioneered the identification of
small molecules that modulate G protein  subunit signaling downstream of GPCRs and have shown that
these molecules have potential therapeutic utility. Here we will further explore the mechanism of action of
these compounds, follow up from results of using these compounds to identify new G protein pathways in cell
migration and identify novel chemical scaffolds for therapeutic development.

## Key facts

- **NIH application ID:** 10142495
- **Project number:** 5R35GM127303-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Alan V. Smrcka
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $592,803
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142495

## Citation

> US National Institutes of Health, RePORTER application 10142495, Understanding and Manipulating Phospholipase C and G Protein beta gamma subunit Signaling Networks (5R35GM127303-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142495. Licensed CC0.

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