Trafficking and gating of epithelial ion channels and their role in hypertension.
Our research is focused on mechanisms that regulate the ion channel ENaC and how defects cause diseases including hypertension. Much of this work is focused on channel ubiquitination and trafficking, and on the signaling pathways that regulate these processes. We discovered that a defect in ENaC endocytosis and lysosomal degradation is responsible for Liddle’s syndrome, an inherited form of hypertension. The causative mutations disrupt a binding site for Nedd4-2, an E3 ubiquitin ligase that catalyzes ENaC ubiquitination. Ubiquitination functions as a signal to induce ENaC endocytosis and targeting to lysosomes for degradation. Thus, defects in this regulation cause a pathological increase in ENaC expression at the cell surface, leading to excessive renal Na+ absorption and hypertension. We have also discovered signaling pathways that control ENaC ubiquitination. A second focus of our work is on mechanisms that control the opening and closing (gating) of ENaC. ENaC has a large highly structured extracellular domain that functions as a receptor to sense a variety of chemical and mechanical signals. These signals induce conformational changes that modulate channel gating. We are working to identify the structure-function relationships that underlie this regulation.
Acetylation stimulates the epithelial sodium channel by reducing its ubiquitination and degradation. Butler PL, Staruschenko A, Snyder PM. J Biol Chem. 2015 May 15;290(20):12497-503. doi: 10.1074/jbc.M114.635540. Epub 2015 Mar 18.
Intersubunit conformational changes mediate epithelial sodium channel gating. Collier DM, Tomkovicz VR, Peterson ZJ, Benson CJ, Snyder PM. J Gen Physiol. 2014 Oct;144(4):337-48. doi: 10.1085/jgp.201411208. Epub 2014 Sep 15.
Regulation of the delta and alpha epithelial sodium channel (ENaC) by ubiquitination and Nedd8. L Y K, McIntosh CJ, Biasio W, Liu Y, Ke Y, Olson DR, Miller JH, Page R, Snyder PM, McDonald FJ. J Cell Physiol. 2013 Nov;228(11):2190-201. doi: 10.1002/jcp.24390.
Ubiquitin-specific peptidase 8 (USP8) regulates endosomal trafficking of the epithelial Na+ channel. Zhou R, Tomkovicz VR, Butler PL, Ochoa LA, Peterson ZJ, Snyder PM. J Biol Chem. 2013 Feb 22;288(8):5389-97. doi: 10.1074/jbc.M112.425272. Epub 2013 Jan 7.
Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II. Sierra A, Zhu Z, Sapay N, Sharotri V, Kline CF, Luczak ED, Subbotina E, Sivaprasadarao A, Snyder PM, Mohler PJ, Anderson ME, Vivaudou M, Zingman LV, Hodgson-Zingman DM. J Biol Chem. 2013 Jan 18;288(3):1568-81. doi: 10.1074/jbc.M112.429548. Epub 2012 Dec 6.