The Ca2+-activated K+ channel, KCa3.1, is required for Ca2+ influx and the subsequent activation of B and T cells. Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated. We recently identified several new signaling molecules that are critical for regulating KCa3.1 channel activity in human CD4+ T cells. We found that: 1) the lipid phophatidylinositol 3 phosphate (PI3P) is required for KCa3.1 channel activity and that the PI3P phosphatase, myotubularin related protein 6 (MTMR6) negatively regulates KCa3.1 by dephosphorylating PI3P; 2) Nucleoside Diphosphate Kinase Beta (NDPK-B), a mammalian histidine kinase, is required for KCa3.1 channel activation by phosphorylating histidine (H) 358 in the carboxyl terminus of KCa3.1; and 3) the histidine phosphatase protein histidine phosphatase-1 (PHPT-1) directly binds and dephosphorylates H358 on KCa3.1 leading to KCa3.1 channel inhibition. These findings provide one of the best examples whereby a mammalian histidine kinase and histidine phosphatase regulates a biological process in mammals. Moreover, these studies identify for the first time that NDPK-B is required for activation of a subset of human CD4+ T cells and that MTMR6 and PHPT-1 function to inhibit activation of these cells. We are currently working to understand the mechanism(s) whereby NDPK-B, PHPT-1, and MTMR6 are regulated in CD4+ T cells. These studies should uncover novel pathways that regulate T cell activation and may identify new mechanisms whereby aberrant activation of these pathways can contribute to autoimmune diseases.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of innumerous fluid-filled cysts in the kidneys and is a common cause of renal failure. Net fluid secretion into renal cysts is driven by transepithelial Cl- secretion mediated by apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels and is an important factor in kidney enlargement. Our recent studies demonstrated that KCa3.1 also plays a critical role in the regulation of CFTR-mediated Cl- secretion and cyst formation in normal human kidney epithelia (NHK) cells and epithelial cells derived from the cysts of ADPKD kidneys. Moreover, we found that treatment of various mouse models of polycystic kidney disease with the KCa3.1 inhibitor, TRAM34, significantly decreased the formation of cysts in these animals. We currently exploring the use of KCa3.1 inhibitors as a potential new therapy to treat patients with ADPKD.
PLCepsilon1 regulates SDF-1alpha-induced lymphocyte adhesion and migration to sites of inflammation
Strazza, Marianne; Azoulay-Alfaguter, Inbar; Peled, Michael; Smrcka, Alan V; Skolnik, Edward Y; Srivastava, Shekhar; Mor, Adam. PLCepsilon1 regulates SDF-1alpha-induced lymphocyte adhesion and migration to sites of inflammation. Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2017 Feb 17;114(10):2693-2698 (2449442)
Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure
Abu-Taha, Issam H; Heijman, Jordi; Hippe, Hans-Jorg; Wolf, Nadine M; El-Armouche, Ali; Nikolaev, Viacheslav O; Schafer, Marina; Wurtz, Christina; Neef, Stefan; Voigt, Niels; Baczko, Istvan; Varro, Andras; Muller, Marion; Meder, Benjamin; Katus, Hugo A; Spiger, Katharina; Vettel, Christiane; Lehmann, Lorenz H; Backs, Johannes; Skolnik, Edward Y; Lutz, Susanne; Dobrev, Dobromir; Wieland, Thomas. Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure. Circulation. 2016 Dec 7;135(9):881-897 (2354352)
Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1
Srivastava, Shekhar; Panda, Saswati; Li, Zhai; Fuhs, Stephen R; Hunter, Tony; Thiele, Dennis J; Hubbard, Stevan R; Skolnik, Edward Y. Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1. eLife. 2016 Aug 19;5:?-? (2219562)
Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4+ T Cells
Panda, Saswati; Srivastava, Shekhar; Li, Zhai; Vaeth, Martin; Fuhs, Stephen R; Hunter, Tony; Skolnik, Edward Y. Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4+ T Cells. Molecular cell. 2016 Aug 04;63(3):457-469 (2191412)
Tumor Anatomy Scoring and Renal Function for Nephron-Sparing Treatment Selection in Patients With Small Renal Masses: A Microsimulation-Based Decision Analysis
Kang, Stella K; Huang, William C; Skolnik, Edward Y; Gervais, Debra A; Braithwaite, R Scott; Pandharipande, Pari V. Tumor Anatomy Scoring and Renal Function for Nephron-Sparing Treatment Selection in Patients With Small Renal Masses: A Microsimulation-Based Decision Analysis. American journal of roentgenology (1976). 2016 Aug;207(2):344-353 (2145162)