The Garcia-Marcos Lab has recently published a study in Molecular Cell (https://doi.org/10.1016/j.molcel.2023.06.006; prepint in: https://www.biorxiv.org/content/10.1101/2023.03.03.529094v1) titled “Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G protein subunits”. The paper describes how different signaling responses triggered by the same neurotransmitter receptor must be carefully scaled to ensure proper brain function. They found that the protein named GINIP shifts the balance of two different G protein sub-species activated simultaneously by G protein-coupled receptors (GPCRs), a large family of surface receptors that respond many neurotransmitters and neuropeptides, including GABA, dopamine, serotonin, or opioids. This mechanism operates in synapses that dampen neurotransmission and, when disabled, results in increased seizure susceptibility in mouse models. These findings have important implications for the fundamental understanding of neuronal communication and for the development of new therapeutic agents that act on GPCRs.
This work was co-led by Jong-Chan Park (Postdoc) and Alex Luebbers (Graduate Student) with collaborations from the Martemyanov Lab at UF Scripps Biomedical Research Institute and the Yano Lab at Northeastern University, and has been highlighted by Molecular Cell (https://doi.org/10.1016/j.molcel.2023.06.034) and Science Signaling (https://www.science.org/doi/10.1126/scisignal.adj6131).
New Publication: The Garcia-Marcos lab, in collaboration with members of the Department of Chemistry at Boston University and the CSIC-CIB in Spain, have published in Proceeding of the National Academy of Sciences (PNAS) …
The Garcia-Marcos lab, in collaboration with members of the Department of Chemistry at Boston University and the CSIC-CIB in Spain, have published in Proceeding of the National Academy of Sciences (PNAS) the discovery of a chemical compound that specifically blocks an aberrant
Human diseases frequently arise from defects in the mechanisms by which external cues are sensed and relayed to the interior of the cell. The proteins most widely targeted by existing therapeutic agents belong to a large family of cell surface receptors named G-protein-coupled receptors (GPCRs), which relay external cues by activating G-proteins in the interior of cells. Here, we report the surprising discovery of a synthetic small molecule that selectively targets G-proteins without compromising their ability to relay signals from GPCRs. Instead, this small molecule disrupts an atypical, GPCR-independent mechanism of G-protein signaling involved in cancer. This work reveals an alternative paradigm in targeting components of a signaling machinery with broad relevance in cellular communication in health and disease.
Congratulations to Arthur Marivin (Garcia-Marcos lab) for his new paper in the Journal of Cell Biology describing how association of DAPLE with PAR polarity complexes at cell-cell junctions coordinates actomyosin assembly in epithelial cells.
Congratulations to Jingyi Zhao, Ph.D. (Garcia-Marcos Lab) who was awarded 2022 Dahod International Scholar.
Jingyi, a postdoc in Dr. Mikel Garcia-Marcos’ laboratory, will characterize a small molecule inhibitor of a novel signaling mechanism that promotes breast cancer metastasis. He has identified a promising candidate molecule, named IGGi-11, that disrupts a protein signaling complex specifically present in metastatic cancer cells. He intends to further confirm the specificity of this molecule in preventing cancer cell invasiveness without overt cytotoxic effects in normal cells, and to work towards developing analog compounds with improved properties in preclinical breast cancer models.
Remi Janicot in the Garcia-Marcos laboratory was awarded an American Heart Association (AHA) predoctoral fellowship for his project "Optical biosensor platforms for the direct interrogation of GPCR signaling in cardiovascular cells”
The goal of this project is to create new experimental tools that can transform how GPCRs are studied. The main benefit over current methods is that these tools can be easily used in cell models that are relevant to study heart or lung disease, which has been an important limitation in the field. These new experimental possibilities would open new doors for the entire cardiovascular research community. The tools designed in this project will allow to study GPCRs with fidelity and precision. This would pave the way to develop new drugs to treat life-threatening cardiac disorders.
Congratulations to Dr. Mikel Garcia-Marcos for receiving the 2022 American Society for Pharmacology and Experimental Therapeutics (ASPET) John J. Abel Award in Pharmacology. The Abel Award is named after the founder of ASPET. It was established in 1946 to stimulate fundamental research in pharmacology and experimental therapeutics by young investigators.
The award will be presented at the ASPET Business Meeting and Awards Presentation during the ASPET Annual Meeting at Experimental Biology 2022 on Saturday, April 2 at 4:30 pm in Philadelphia. Additionally, Dr. Garcia-Marcos will deliver the Abel Award Lecture titled The Secret Life of G Proteins to open the 2022 annual meeting on Saturday, April 2 at 10:00 am in Philadelphia.
Congratulations to Mikel Garcia-Marcos on his promotion to Full Professor of Biochemistry!
The Garcia-Marcos Lab investigates signal transduction mechanisms with the ultimate goal of elucidating the molecular basis of human diseases and developing novel therapeutic approaches.
The Garcia-Marcos laboratory has discovered that heterotrimeric G-proteins, which are critical molecular switches in cellular communication processes, can trigger different responses in cells depending on the type of protein that activates them.
Heterotrimeric G-proteins are typically activated by G-protein-coupled receptors (GPCRs), which are the target for over one-third of drugs approved for use in the clinic. But G-proteins can also be activated by other proteins that are not GPCRs, a mechanism with important implications for human physiology and disease. The Garcia-Marcos laboratory has used an innovative approach to dissect and compare the consequences of G-protein stimulation by different activators, including GPCRs and various non-GPCR proteins. The approach leveraged a recently developed type of biosensors capable of detecting different forms of active G-proteins in living cells in real time. These were combined with engineered G-protein activator constructs that could be turned on at will with an exogenous synthetic chemical.
The main conclusion is that, contrary to previous beliefs, GPCR and non-GPCR activators elicit different forms of G-protein activation in cells. These findings have important implications in our understanding of pharmacologically actionable signaling hubs in cells, which could be leveraged to envision and design new therapeutic agents.
You can read the article here:
Garcia-Marcos M. Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators. Elife. 2021 Mar 31;10:e65620. PMID: 33787494 https://pubmed.ncbi.nlm.nih.gov/33787494/
The Garcia-Marcos laboratory has recently published a new study in the journal Science Signaling. In this study, the authors characterized how cancer-associated mutations in a family of negative regulators of G proteins affect the ability of these regulators to modulate G protein activity. Many of these mutations turn out to be deleterious for the G protein regulatory function. In the words of the journal's Editor:
"Mutations in the genes encoding the α subunits of heterotrimeric G proteins are associated with cancer. In particular, mutations that prevent the Gα subunits from hydrolyzing GTP, thus rendering them constitutively active, are pro-oncogenic. DiGiacomo et al. surveyed cancer-associated mutations in regulator of G protein signaling (RGS) proteins, which are physiological inhibitors of G proteins. Through bioinformatics analysis, genetic interaction studies in yeast, and functional assays in mammalian cells, the authors showed that many cancer-associated RGS mutants fail to inhibit G protein signaling because of reduced protein stability or impaired interactions with their targets. With these tools, further cancer-associated mutations in RGS proteins can be characterized."
This work was spearheaded by the former Garcia-Marcos' laboratory postdoc Vincent DiGiacomo, who is currently working in the Cambridge biotech company DeepBiome, with the help of other laboratory members, including two undergraduate students from Boston University. The entire study was carried out in the Department of Biochemistry.