Mikel Garcia-Marcos
· Professor of Biochemistry and BiologyBoston University · Biology
Active 2003–2026
About
Mikel Garcia-Marcos is a Professor of Biochemistry and Biology at Boston University, with a PhD in Biochemistry from the University of the Basque Country. His research focuses on understanding the mechanisms and consequences of cell communication via heterotrimeric G-proteins, which are major intracellular hubs of signaling with significant biomedical relevance. His laboratory aims to discover and characterize new components of the G-protein regulatory network, impacting cellular communication in health and disease. The work has direct implications for cancer, embryonic development defects, and neurological disorders. Garcia-Marcos employs a multi-scale approach that integrates molecular, cellular, and organismal level investigations, utilizing biochemistry, cell biology, and genetics across various experimental systems including purified proteins, cultured cells, and model organisms such as mice, frogs, and zebrafish. He is also interested in developing novel tools like optical biosensors and chemogenetic/optogenetic tools to detect and manipulate signaling activity in cells.
Selected publications
Journal of Pharmacology and Experimental Therapeutics · 2026-05-01
articleSenior authorInhibitory probes for spatiotemporal analysis of Gαs protein signaling
Nature Chemical Biology · 2026-02-03 · 1 citations
articleSenior authorA Region-Specific Role of Gαz in Opioid Analgesia and Tolerance (Abstract ID: 224350)
Journal of Pharmacology and Experimental Therapeutics · 2026-05-01
articleAbstract 3796 Development of a peptide-based probe for inhibiting Gαs signaling
Journal of Biological Chemistry · 2026-05-01
articleOpen accessSenior authorJournal of Pharmacology and Experimental Therapeutics · 2026-05-01
articleSenior authorJournal of Pharmacology and Experimental Therapeutics · 2026-05-01
articleSenior authorJournal of Pharmacology and Experimental Therapeutics · 2025-03-01
articleOpen accessSenior authorSuccinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism
FEBS Journal · 2025-01-21 · 8 citations
articleOpen accessSuccinate is a pivotal tricarboxylic acid cycle metabolite but also specifically activates the G i ‐ and G q ‐coupled succinate receptor 1 (SUCNR1). Contradictory roles of succinate and succinate‐SUCNR1 signaling include reports about its anti‐ or pro‐inflammatory effects. The link between cellular metabolism and localization‐dependent SUCNR1 signaling qualifies as a potential cause for the reported conflicts. To systematically address this connection, we used a diverse set of methods, including several bioluminescence resonance energy transfer‐based biosensors, dynamic mass redistribution measurements, second messenger and kinase phosphorylation assays, calcium imaging, and metabolic analyses. Different cellular metabolic states were mimicked using glucose (Glc) or glutamine (Gln) as available energy substrates to provoke differential endogenous succinate (SUC) production. We show that SUCNR1 signaling, localization, and metabolism are mutually dependent, with SUCNR1 showing distinct spatial and energy substrate‐dependent G i and G q protein activation. We found that Gln‐consumption associated with a higher rate of oxidative phosphorylation causes increased extracellular SUC concentrations, accompanied by a higher rate of SUCNR1 internalization, reduced miniG q protein recruitment to the plasma membrane, and lower Ca 2+ signals. In Glc, under basal conditions, SUCNR1 causes stronger G q than G i protein activation, while the opposite is true upon stimulation with an agonist. In addition, SUCNR1 specifically interacts with miniG proteins in endosomal compartments. In THP‐1 cells, polarized to M2‐like macrophages, endogenous SUCNR1‐mediated G i signaling stimulates glycolysis, while G q signaling inhibits the glycolytic rate. Our results suggest that the metabolic context determines spatially dependent SUCNR1 signaling, which in turn modulates cellular energy homeostasis and mediates adaptations to changes in SUC concentrations.
Abstract Or202: Multiscale Platform Identifies Novel Therapeutic Targets for Fibrosis
Circulation Research · 2025-08-01
articleFibrosis is characterized by excessive extracellular matrix (ECM) deposition, leading to organ stiffness and eventual dysfunction. However, the considerable species differences, lack of counter-screening for toxicity, and the inability to recapitulate the complex microenvironment in 2D cells have led to the failure of promising preclinical drugs in clinical trials. Human induced pluripotent stem cell (iPSC) technology has been increasingly utilized for disease modeling, drug screening, and toxicity testing, enabling precision medicine. To identify novel antifibrotic therapies, I established a multiscale platform that integrates human iPSCs, tissue engineering, and animal models (Figure 1) . First, I developed a protocol to derive cardiac fibroblasts (CFs) from human iPSCs, creating an unlimited cell source to study cardiac fibrosis. This method produces homogenous iPSC-CFs that remain quiescent and sensitive to profibrotic stimuli. For drug screening, I generated ACTA2 reporter iPSC lines to monitor MyoFB activation. To recapitulate the fibrosis-induced contractile dysfunction in vitro , I generated a 3D iPSC-derived engineered heart tissue (EHT) model composed of iPSC-cardiomyocytes (CMs) and iPSC-CFs. Profibrotic stimulation reduced contraction and relaxation velocity, along with increased passive tension, demonstrating that this EHT model faithfully recapitulated the characteristics of cardiac fibrosis in vivo . Leveraging the multiscale platform, I performed a high-throughput screening utilizing a library of ~10,000 compounds on reporter iPSC-CFs, and conducted counter-screenings in iPSC derived CMs and endothelial cells (ECs) to exclude cardiotoxicity. From the bioactive compound library, I identified an adenosine receptor (AR, family A GPCR) antagonist as a potent treatment for cardiac fibrosis. Adenosine promotes fibrosis in multiple organs. Although GPCRs are the largest family of druggable proteins encoded in the human genome, progress in targeting them has been hindered by the lack of tools to reliably measure their signaling modalities. Leveraging state-of-the-art biosensors capable of recording the activity of endogenous GPCRs, I discovered that atypical, Gβγ-dependent GPCR signaling triggered by AR underlies the antifibrotic effects. In summary, the reliable multiscale platform not only AR-triggered Gβγ signaling as a promising target, but also provides a broad approach to discovering safe and effective drugs for fibrosis therapy.
Development · 2025-11-28 · 2 citations
articleOpen accessAdherens junctions (AJs) stabilize cell contacts by coupling adhesion molecules to the cytoskeleton. AJ proteins have been studied extensively in epithelia, but less is known about their roles in other cell types. Here, we describe a role for AJ proteins in C. elegans glia. Previously, we showed that C. elegans glia use the adhesion molecule SAX-7/L1CAM to anchor the dendritic endings of URX and BAG sensory neurons at the nose during embryo elongation, allowing their dendrites to stretch to their full lengths. Using cell-specific rescue and depletion experiments, we show that the AJ proteins MAGI-1 and HMR-1/Cadherin also act in glia to promote URX and BAG dendrite extension. MAGI-1 is a multi-PDZ domain protein that can simultaneously interact with PDZ-binding (PB) motifs in SAX-7 and HMP-2/β-catenin thus potentially bridging SAX-7 to the cadherin-catenin complex. The SAX-7 PB motif also binds AFD-1/afadin. Double-mutant analyses indicate that many of these players act redundantly, consistent with parallel interactions among them. As MAGI-1, HMR-1 and AFD-1 are all found in epithelial AJs, we propose that an AJ-like complex in glia promotes dendrite extension.
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