Alan Smrcka

I received my Ph.D. in Biochemistry from the University of Arizona in 1990 and did postdoctoral work in the Department of Pharmacology at the University of Texas Southwestern Medical Center where I began my work on G protein-coupled receptors (GPCRs) and G protein signaling. In 1994 I took a faculty position at the University of Rochester School of Medicine in the Department of Pharmacology and Physiology. In 2016 I moved to the Department of Pharmacology at the University of Michigan where I hold the Benedict Lucchesi Collegiate Chair in Cardiovascular Pharmacology and am Associate Chair of Research.

I have served on standing NIH study sections from 2002-2006 and from 2014-2018 including chairing the “Molecular and Integrative Signal Transduction” study section from 2016-2018. I have also served as ad hoc on various study sections from 2018-2021. I am currently an Associate Editor at Molecular Pharmacology and have served in various executive positions in the American Society of Pharmacology and Experiment Therapeutics (ASPET) and was recently selected as an ASPET fellow. I am currently Chair of the “Phosphorylation and G protein-Mediated Signaling Networks” Gordon Research Conference to be held in June of 2024.

My laboratory studies GPCR-mediated signal transduction and uses a combination of biochemical, biophysical, cell biological, and in vivo methods to understand the signaling pathways regulated by GPCRs. One major area research for many years has been on understanding mechanisms for regulation of phospholipase C isoforms downstream G protein coupled receptors (GPCRs). We have made contributions to identifying G protein regulators of PLC isoforms (Galphaq and Gbeta/gamma subunits) and demonstrating direct regulatory interactions. After discovery of a novel PLC isoform, PLCepsilon, we moved on to determine physiological functions of GPCR regulated PLCepsilon through the development of a PLCepsilon knockout mouse. Through our own work, and those of our collaborators, we established several novel paradigms in GPCR-dependent PLC regulation that have impacted multiple areas of biology including regulation of cardiac contraction, cardiac hypertrophy, endocrine secretion, and inflammation. These studies also led to the finding that PLCepsilon in the heart is selectively regulated by Golgi resident beta1 adrenergic receptors.
Another area of long-standing interest is in signal transduction by G protein beta/gamma subunits where we have investigated molecular mechanisms of binding partner recognition by Gbeta/gamma subunits, establishing the idea that Gbeta/gamma subunits have a protein interaction “hot spot” capable of adapting to multiple binding partners. An outgrowth of these studies was the development of small molecule pharmacological approaches that selectively block Gbeta/gamma-dependent activation of downstream binding partners; ie. blockade of PLCbeta activation but not inwardly rectifying potassium channel activation. These molecules have been used as probes to establish Gbeta/gamma signaling as a viable in vivo pharmacological target.
Most recently we have directed our focus to identifying new G protein alpha subunit signaling pathways using proximity labeling proteomics. This approach works very well at identifying known interaction partners and has revealed multiple new proteins and pathways potentially regulated by G proteins. These include proteins expected to be at the plasma membrane but also excitingly identifies novel interactions in intracellular compartments including the nucleus. Intracellular signaling by GPCRs is a hot topic in the field but specific roles for intracellular G proteins remains somewhat unexplored. We are very excited about this new approach and feel that it has already revealed unexpected interaction networks that remain to be explored in more depth.