Lincoln R. Potter, PhD

Professor, and Biophysics Department of Biochemistry, Molecular Biology

Lincoln R. Potter

Contact Info

potter@umn.edu

Office Phone 612-624-7251

Fax 612-624-0432

Professor, and Biophysics Department of Biochemistry, Molecular Biology

Faculty, PhD Program in Biochemistry, Molecular Biology and Biophysics

Faculty, PhD Program in Integrative Biology and Physiology


Summary

Expertise

Signal transduction, Natriuretic peptides, Guanylyl cyclase receptors, cGMP, Hypertension, Heart failure, Bone growth

Research

Research Summary/Interests

Our research focuses on the natriuretic peptide family and their cognate receptors, guanylyl cyclase-A (GC-A) and GC-B (Fig. 1). Both receptors are single membrane-spanning enzymes that consist of an extracellular ligand binding domain and intracellular kinase homology regulatory domain and cGMP synthesizing GC domain. Atrial natriuretic peptide (ANP) and brain natriuretic peptide decrease blood pressure and inhibit cardiac hypertrophy by activating GC-A. C-type natriuretic peptide (CNP) activation of GC-B regulates oocyte meiosis and stimulates long bone growth.

Initial studies on post translational modifications of these enzymes indicated that phosphorylation and dephosphorylation are required for receptor activation and inactivation, respectively (Potter and Garbers, JBC, 1992, Potter, Biochemistry, 1998, Potter and Hunter, MCB, 1998, Potter and Hunter, JBC, 1998). Subsequent studies demonstrated that hormones that antagonize the actions of natriuretic peptides reduce signaling through this pathway by stimulating natriuretic peptide receptor dephosphorylation (Abbey and Potter, JBC, 2002, Abbey-Hosch et. al, Hypertension, 2004, Potthast et al, JBC, 2004). Later, we determined that GC-A, but not GC-B, is inactivated in failed murine and human hearts (Dickey et. al, Endocrinology, 2007, Dickey et. al, JMCC, 2013). We also found that N-linked glycosylation, another post-translational modification, is required for GC-B signaling and that missense mutation that inhibit glycosylation of GC-B cause dwarfism (Dickey et. al, JBC, 2016).

Phosphomimetic forms of GC-A and GC-B that cannot be inactivated by dephosphorylation were engineered (Yoder et al. PLoS One, 2012, Otto et al, Mol. Pharmacol, 2017). In collaboration with Dr. Laurinda Jaffe's group, we produced mice expressing glutamate-substituted natriuretic peptide receptors that cannot be inactivated by dephosphorylation. Initial studies on GC-B7E/7E demonstrated that receptor dephosphorylation mediates luteinizing hormone-dependent resumption of meiosis in oocytes (Shuhaibar et al, Dev. Biol., 2016). The GC-B7E/7E mice also have longer bones than wild type mice! To determine the contribution of GC-B dephosphorylation to human dwarfism, we generated the fibroblast growth factor receptor (FGFR)3G374R/+ mouse line that mimics the mutation that accounts for most cases of human dwarfism (small mouse in Fig. 2). The FGFR3G374R/+ mice are being crossed with the GC-B7E/7E mice to determine the contribution of GC-B dephosphorylation to (FGFR)3G374R/+ dependent dwarfism. In addition, a mouse expressing two alleles of a dephosphorylation resistant form of GC-A called GC-A8E/8E was made and will be tested for resistance to heart failure.

Studies on non-covalent regulation of GC-A and GC-B determined that ATP allosterically activates these enzymes by binding a site in the catalytic domain (Antos et al, JBC, 1995, Antos and Potter, AJP, 2007, Robinson and Potter, JBC, 2011, and Robinson and Potter, 2012). New data indicate that GC-A and GC-B contain a second ATP binding site in their kinase homology domains (Edmund and Potter, in preparation). GC-B mutations that cause skeletal overgrowth take advantage of this type of regulation by mimicking an allosterically activated conformation of the enzyme (Dickey et al, JBC, 2017).