Current Research Interests:

Cardiovascular disease is a growing problem worldwide and the leading cause of death in the United States. Phospholipase C (PLC) enzymes, in particular PLCβ and PLCε, are essential for normal cardiovascular function and generate the second messengers diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3), which in turn lead to increases in intracellular calcium and activation of protein kinase C. Abnormally high levels of DAG and IP3 can cause cardiac arrhythmias, hypertrophy, and heart failure. PLCβ and PLCε respond to various extracellular signals that serve to regulate the production of these second messengers. PLCβ is activated downstream of G protein-coupled receptors, such as the angiotensin receptor, via direct interactions with the heterotrimeric G protein subunits Gαq and Gβγ. PLCε integrates and amplifies signals from both G protein-coupled receptors and receptor tyrosine kinases via direct interactions with small molecular weight G proteins, such as Ras, and the Gβγ heterodimer. The goals of our lab are to understand the molecular mechanisms regulating PLCβ and PLCε under basal and activating conditions. These studies incorporate biochemical and cell-based functional assays along with an innovative combination of X-ray crystallography and electron cryo-microscopy. Taken together, these studies will provide much needed insight into two key enzymes that contribute to cardiovascular function and disease, and will ultimately aid in the identification and development of novel therapeutics that modulate signaling by these enzymes.

Selected Publications:

Garland-Kuntz, E.E., Vago, F.S., Van Camp, M., Sieng, M., Chakravarthy, S, Blaine, A., Corpstein, C., Jiang, W., and Lyon, A.M. Direct Observation of Conformational Dynamics of the PH Domain in Phospholipase Cε and β. In revision

Madukwe, J.C., Garland-Kuntz, E.E., Lyon, A.M., and Smrcka, A.V. Direction Regulation of PLCε by G Protein Gβγ Subunits. J. Biol. Chem. 293 (17), 6387-6397 (2018). PMID: 29535186.

Hudson, B.N., Hyun, S-H., Thompson, D.T., and Lyon, A.M. Phospholipase Cβ3 Membrane Adsorption and Activation is Regulated by its C-terminal Domains and PIP2. Biochemistry 56, 5604-5614 (2017). PMID: 28945450

Ben-Salem, S., Nara, S., Lyon, A.M., Al-Shamsi, A., Islam, B., Akawi, N., John, A., Thachillath, P., David, V., Ali, B.R., and Al-Gazali, L. Defect in phosphoinositide signaling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. J. Med. Genet. 55(2), 122-130 (2018). PMID: 29122926