# Understanding and Manipulating G Protein α Subunit and Phospholipase C Signaling Networks

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $536,377

## Abstract

My laboratory is interested signal transduction by G protein-coupled receptors (GPCRs) with a specific focus on
the second messenger pathways downstream and how they drive physiology and pathophysiology in specific
cells and tissues. GPCRs signaling pathways are ubiquitous and conserved, with cellular responses determined
by 1) the specific GPCRs and G proteins expressed in the cell and 2) how the cells decode signals generated
by these receptors. My career has been focused on uncovering novel cellular signal transduction mechanisms
at a cellular and molecular level that move beyond a canonical GPCR paradigm where individual GPCRs simply
couple to 3 major signal transduction pathways, phospholipase C activation, adenylyl cyclase regulation, and
RhoGEF stimulation, and the cells do the rest. In this renewal application we propose to capitalize on advances
made in the previous funding in two general areas 1) Proteomic analysis of G protein α subunit-mediated signal
transduction pathways and; 2) intracellular signaling by β-adrenergic receptors (βARs) and phospholipase C in
cardiac myocytes. The first project is based on the striking success of our proteomic screens using proximity
labeling mass spectrometry that maintains cell context while identifying protein-protein interactions. We propose
to characterize two novel G protein targets from these screens that play roles in regulation of chromatin
remodeling and gene expression through mechanisms that would be unprecedented downstream of GPCRs. In
addition, we propose to leverage this method to identification of new signal pathways mediated by G proteins as
GPCRs move through the endocytic and recycling pathways. Intracellular signaling by GPCRs is a new and
emerging paradigm in the field but much less is known about intracellular G protein and effector engagement by
internal GPCRs. The second direction will be to follow up our finding that phospholipase C activity at the Golgi
apparatus is regulated by intracellular Golgi localized β1-adrenergic receptors (β1ARs). The proposed
experiments will test the hypothesis that intracellular β1ARs regulate a unique subset of genes in cardiac
myocytes related to cardiac hypertrophy through regulation of phosphoinositide hydrolysis at the Golgi
apparatus. We will determine what signaling pathways are regulated by Golgi β1ARs beyond the Epac-PLCε-
PKD signaling pathway that we have previously described. Finally, we will investigate the mechanisms for
pathways downstream of β2ARs that oppose hypertrophic β1AR signaling at the Golgi. This is exciting because
β1AR signaling in vivo is pro-hypertrophic while β2AR signaling is protective and will uncover a novel mechanism
for protective β2AR signaling. Overall, these experiments will reveal novel signaling mechanisms that have
implications for therapies that target GPCRs.

## Key facts

- **NIH application ID:** 10893320
- **Project number:** 5R35GM127303-07
- **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:** 2024
- **Award amount:** $536,377
- **Award type:** 5
- **Project period:** 2018-05-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893320

## Citation

> US National Institutes of Health, RePORTER application 10893320, Understanding and Manipulating G Protein α Subunit and Phospholipase C Signaling Networks (5R35GM127303-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10893320. Licensed CC0.

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