Dissecting the spatiotemporal encoding of gas… (F31HL188983) – Project Grant to Trustees Of Boston University

Abstract: Significance & innovation: heterotrimeric g proteins (gαβγ) are molecular switches that transduce incoming signals from g protein-coupled receptors (gpcrs), the largest family of surface receptors in humans and the target for over one-third of clinically used drugs. The concept of g protein-mediated signal transduction from gpcrs emerged from the study of the action of hormones like adrenaline/epinephrine on β-adrenoceptors (βars) to induce the generation of the second messenger camp through the action of the prototypical g protein GS on its effector adenylyl cyclase. Although the canonical view of gpcr-g protein signaling was that g proteins are exclusively activated by receptors at the plasma membrane, recent evidence has shown that this may also occur at intracellular membranous organelles like endosomes or the golgi apparatus, among others. Compartmentalized gpcr signaling is particularly relevant in cardiomyocytes, which express receptors for adrenaline with critical functions in health and disease. Emerging evidence indicates that intracellular gpcrs are implicated in both acute and long-term responses in cardiomyocytes. More specifically, second messenger generation at different subcellular locations in cardiomyocytes has been shown to regulate different physiological responses, such as contraction, relaxation, and even cardiac hypertrophy in heart failure. There still remains, however, a lack of understanding of the process of signal transduction via g proteins at intracellular membranes- i.e., how does activation of g proteins at different subcellular locations encoded cardiomyocyte responses? This GAP in knowledge is largely due to a lack of tools to specifically and precisely inhibit or activate g protein signaling at different subcellular locations. The goal of this project is to develop and implement new approaches to systematically define how GΑS activity in different subcellular compartments triggers molecular and cellular responses. I will use these tools to address the impact of subcellular compartmentalization in long- standing questions about the different functional responses to adrenaline in cardiomyocytes. Approach: i will tackle this question from two complementary perspectives. In aim 1, i will investigate the relationship of sufficiency between inputs (i.e., activation of GΑS at discrete subcellular locations) and outputs (i.e., changes in signaling at the molecular level and in behavior at the cellular level) by leveraging a novel chemogenetic approach to activate GΑS directly in different subcellular compartment without the involvement of gpcrs. In contrast, aim 2 will investigate the necessity of g protein activation events at specific subcellular compartments in the context of naturally-occurring inputs (i.e., gpcr-mediated activation) leading to molecular and functional outputs. For this, i will leverage genetically-encoded GΑS inhibitors and a newly developed genetic tool, which allow me to block gpcr-g protein signaling at the subcellular scale and with high temporal resolution. Potential impact: this project will provide systematic and definitive evidence on the consequences and mechanisms of intracellular gpcr signaling, and generate tools with transformative potential.

Dissecting the spatiotemporal encoding of gas signaling in cardiomyocytes

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