Financial Support of Membrane Trainees:

Paul A. Welling, M.D.
Professor

Department of Physiology
School of Medicine

410-706-3851

pwelling@umaryland.edu

Research

The Welling laboratory studies the molecular genetics and physiology of electrolyte transport disorders. The movement of ions across cell membranes is exquisitely controlled for a diverse variety of vital body functions. The normal electrical activity of nerve and brain cells, the control of blood pressure by the kidney and the maintenance heart rhythm represent just a few examples. Defects in ion transport molecules and their regulators give rise to serious, even lethal, human diseases. A major thrust of investigations in the Welling laboratory involves molecular genetic dissections of inherited disorders of membrane transport, so-called “channelopathies” or “transporteropathies.”

We are particularly interested in understanding the regulatory mechanisms which normally control the number, location and activity of transport molecules and that go awry in human disease. We employ a multidisciplinary approach, combining tools of molecular genetics, cellular biology, biochemistry, and physiology with state-of-the-art imaging techniques. A key strategy involves defining regulator or localization signals that are embedded within the structures of ion channels and salt-transporters; discovering the intracellular machinery that decodes the signals; and understanding the molecular signaling pathways that influence the interaction between the two. Genetically modified animal models are used to translate our discoveries about fundamental mechanisms to higher-level systems in vivo.

Our focus has been on understanding how potassium channels in the heart, kidney and nervous system are regulated in health and dysfunction in disease, providing ideal models to investigate fundamental molecular mechanisms with direct clinical impact. One research program is focused on unraveling the mechanisms that control salt balance and blood pressure in health and contribute to electrolyte disorders and hypertension in kidney disease. Our studies in the heart are leading to a molecular understanding of certain hereditary arrhythmias.

Research Topics :

Molecular Cell Biology:

Cell Signaling
Endocytosis
Exocytosis
Mechanisms of Cell Polarity
Regulation of Membrane Trafficking
Scaffolding Proteins
Secretory Pathway

Physiology, Systems Biology and Pathophysiology

Ion Channels and Transporters
Molecular Genetics of Membrane Transport and Excitability Disorders
Molecular Mechanisms of Trafficking Defects in Cardiac Arrhythmias
Molecular and Cell Biology of the Kidney
Regulation of Salt Balance and Blood Pressure

Lab Techniques

Recombinant DNA techniques, including cloning, mutagenesis and heterologous expression, are used extensively. Protein-Protein interactions are studied using recombinant protein biochemistry, yeast two hybrid techniques and proteomic approaches. We also employ a most state-of-the art cell biological techniques, including confocal microscopy and live cell imaging techniques. Physiological and Cell Biological Studies in Genetically modified mice. Transgenetic and knockout. We employ a wealth of electrophysiological techniques, such as patch-clamp analysis (single channel and whole cell), two-microelectrode voltage clamp, and epithelial monolayer voltage clamp.

Publications

Recent Representative Publications

Yoo D, Fang L, Mason A, Kim B.Y. and P.A. Welling. A phosphorylation-dependent export structure in ROMK (KIR 1.1) channel overrides an ER- localization signal. J Biol Chem. 2005;280(42):35281-9.

James B. Wade*, Liang Fang*, Jie Liu*, Dimin Li*, Chao-Ling Yang†, Arohan R. Subramanya†, Djikolngar Maouyo*, Amanda Mason*, David H. Ellison†, and P. A. Welling* WNK1 Kinase Isoform Switch Regulates Renal Potassium Excretion Proc. Natl. Acad. Sci. USA, 2006. 30;103(22):8558-63.

Christine Alewine*, Olav Olsen*, James B. Wade, P. A. Welling, TIP-1 has PDZ Scaffold Antagonist Activity, Mol Biol Cell. 2006 Oct;17(10):4200-11

Donhui Ma, Sean Tang, Terry Rogers, P.A. Welling, The Andersen-Tawil Syndrome Mutant Kir2.1 (V302M) Alters the G-loop cytoplasmic K+ Conduction Pathway, J Biol Chem, 2007;282(8):5781-9

Olsen, O., L. Funke, J.-f. Long, M. Fukata, T. Kazuta, J.C. Trinidad, K.A. Moore, H. Misawa, P.A. Welling, A.L. Burlingame, M. Zhang, and D.S. Bredt Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice, J. Cell Biol. 2007 179(1):151-64

JAlewine, C, Bo-Y Kim, Vandana Hegde and P.A. Welling, Basolateral Membrane Expression of Kir 2.3 Requires Lin-7 L27 Domain Interaction With A Polarized Scaffold, Am J Physiology, Cell 2007 Dec;293(6):C1733-41.

Mason A.K, Jacobs, B.E, P.A. Welling AP-2 Dependent Internalization of Kir2.3 Is Driven By A Non-Canonical Di-Hydrophobic Signal, J Biol Chem, 2008 Mar 7;283(10):5973-84

Wang Y, O'Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, Shi X, Pan L, Rampersaud E, Shen H, Kim JD, Subramanya AR, Steinle NI, Parsa A, Ober CC, P. A. Welling, Chakravarti A, Weder AB, Cooper RS, Mitchell BD, Shuldiner AR, Chang YP. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31.

Subramanya, Arohan R., Wade, JB, P. A. Welling, WNK4 Kinase Diverts Newly Synthesized NCC Cotransporters into the Lysosomal Pathway and Stimulates AP-3 Clathrin Adaptor Interaction, J Biol Chem. 2009 Apr 28. 2009 Jul 3;284(27):18471-80.

Fang, L, Bo-Young Kim Wade, J. B., P. A. Welling, The ARH Adaptor Protein Targets the Kidney ROMK Potassium Secretory Channel for Endocytosis, In Press, Journal of Clinical Investigation

Personal History

I graduated from the University of Kansas Medical School in 1988. I then began postdoctoral training at Yale University, School of Medicine in the laboratory of Dr. Gerhard Giebisch.

During that time, I studied the cellular and molecular basis for salt handing. I joined the University of Maryland, School of Medicine in 1993 as an assistant professor. I have enjoyed continuous funding from the National Institutes of Health since that time.

I am presently a Professor of Physiology and Fellow of the American Heart Association

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