University of Pittsburgh Department of Cell Biology

Butterworth Lab

Our major research interest is investigating the regulation of ion transport in epithelial tissues of the kidney and airway. We have particular expertise studying the epithelial sodium channel (ENaC) and its regulation by trafficking and recycling. Studies focus on two tissues, the distal kidney nephron where upregulation of the channel is associated with volume expansion and hypertension, and human airway where ENaC hyperactivity is linked to cystic fibrosis. The main focus is understanding the cellular regulation of these sodium transporters and channels. The research could therefore be classified as cell physiology.

Our current work investigates how distal nephron transporters respond to a variety of signals including hormonal regulation via microRNAs. We have identified a subset of microRNAs that are specifically regulated by steroid hormones (aldosterone) and demonstrated that changes in microRNA expression directly alters sodium transport in the kidney. We use a range of techniques to investigate the effect of aldosterone on miRNA regulation in the kidney, and identify new protein targets that regulate ENaC. In ongoing work we have expanded this analysis to incorporate a number of hormonal signals in the kidney including vasopressin, insulin and related steroid hormones. Our lab uses a range of techniques to address these questions including RNA-Seq (microRNA deep-seq), genomic and proteomic analysis, in vitro and in vivo knockout studies, electrophysiological recordings of ion transport, biochemical and imaging approaches to study protein regulation and trafficking and mouse metabolic and diet studies.

  1. Klemens CA, Edinger RS, Kightlinger L, Liu X, Butterworth MB. Ankyrin G Expression Regulates Apical Delivery of the Epithelial Sodium Channel (ENaC).. J Biol Chem. 2017 Jan 6;292(1):375-385. doi: 10.1074/jbc.M116.753616. PubMed PMID: 27895120;
  2. Liu X, Edinger RS, Klemens CA, Phua YL, Bodnar AJ, LaFramboise WA, Ho J, Butterworth MB. A MicroRNA Cluster miR-23-24-27 Is Upregulated by Aldosterone in the Distal Kidney Nephron Where it Alters Sodium Transport.. J Cell Physiol. 2017 Jun;232(6):1306-1317. doi: 10.1002/jcp.25599. PubMed PMID: 27636893;
  3. Edinger RS, Bertrand CA, Rondandino C, Apodaca GA, Johnson JP, Butterworth MB. The epithelial sodium channel (ENaC) establishes a trafficking vesicle pool responsible for its regulation. PLoS One. 2012;7(9):e46593. doi: 10.1371/journal.pone.0046593. Epub 2012 Sep 28. PubMed PMID: 23029554; PubMed Central PMCID: PMC3460899.
  4. Butterworth MB, Zhang L, Heidrich EM, Myerburg MM, Thibodeau PH. Activation of the epithelial sodium channel (ENaC) by the alkaline protease from Pseudomonas aeruginosa. J Biol Chem. 2012 Sep 21;287(39):32556-65. Epub 2012 Aug 2. PubMed PMID: 22859302; PubMed Central PMCID: PMC3463336.
  5. Butterworth MB, Edinger RS, Silvis MR, Gallo LI, Liang X, Apodaca G, Frizzell RA, Johnson JP. Rab11b regulates the trafficking and recycling of the epithelial sodium channel (ENaC). Am J Physiol Renal Physiol. 2012 Mar 1;302(5):F581-90. doi: 10.​1152/​ajprenal.​00304.​2011. Epub 2011 Nov 30. Erratum in: Am J Physiol Renal Physiol. 2012 Jul;303(1):F163. Fizzell, Raymond A [corrected to Frizzell, Raymond A]. PubMed PMID: 22129970; PubMed Central PMCID: PMC3353647.
  6. Liang X, Butterworth MB, Peters KW, Frizzell RA. AS160 modulates aldosterone-stimulated epithelial sodium channel forward trafficking. Mol Biol Cell. 2010 Jun 15;21(12):2024-33. doi: 10.1091/mbc.E10-01-0042. Epub 2010 Apr 21. PubMed PMID: 20410134; PubMed Central PMCID: PMC2883946.
  7. Myerburg MM, Harvey PR, Heidrich EM, Pilewski JM, Butterworth MB. Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking. Am J Respir Cell Mol Biol. 2010 Dec;43(6):712-9. doi: 10.1165/rcmb.2009-0348OC. Epub 2010 Jan 22. PubMed PMID: 20097829; PubMed Central PMCID: PMC2993091.
  8. Butterworth MB, Edinger RS, Ovaa H, Burg D, Johnson JP, Frizzell RA. The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling of the epithelial sodium channel. J Biol Chem. 2007 Dec 28;282(52):37885-93. Epub 2007 Oct 29. PubMed PMID: 17967898.
  9. Hill WG, Butterworth MB, Wang H, Edinger RS, Lebowitz J, Peters KW, Frizzell RA, Johnson JP. The epithelial sodium channel (ENaC) traffics to apical membrane in lipid rafts in mouse cortical collecting duct cells. J Biol Chem. 2007 Dec 28;282(52):37402-11. Epub 2007 Oct 10. PubMed PMID: 17932048.
  10. Myerburg MM, Butterworth MB, McKenna EE, Peters KW, Frizzell RA, Kleyman TR, Pilewski JM. Airway surface liquid volume regulates ENaC by altering the serine protease-protease inhibitor balance: a mechanism for sodium hyperabsorption in cystic fibrosis. J Biol Chem. 2006 Sep 22;281(38):27942-9. Epub 2006 Jul 26. PubMed PMID: 16873367.
  11. Butterworth MB, Frizzell RA, Johnson JP, Peters KW, Edinger RS. PKA-dependent ENaC trafficking requires the SNARE-binding protein complexin. Am J Physiol Renal Physiol. 2005 Nov;289(5):F969-77. Epub 2005 Jun 21. PubMed PMID: 15972388.
  12. Butterworth MB, Edinger RS, Johnson JP, Frizzell RA. Acute ENaC stimulation by cAMP in a kidney cell line is mediated by exocytic insertion from a recycling channel pool. J Gen Physiol. 2005 Jan;125(1):81-101. PubMed PMID: 15623897; PubMed Central PMCID: PMC2217480.
Postal Address:
University of Pittsburgh
Department of Cell Biology
S314 BST-South
Telephone:  412-383-8591  
Fax: 412-648-8330  
Email:  michael7@pitt.edu