Ion channels, cardiac arrhythmia, sudden death, stroke, neurotoxins, hypoxia, single-molecule spectroscopy
New Investigator Award (1994, Donaghue Foundation)
Yale University, Master of Arts Privatum (2001, honorary degree)
E. Mead Johnson Award (2001, Society for Pediatric Research)
Distinguished Clinical Scientist Award (2001, Doris Duke Charitable Foundation)
Pritzker Scholar (2004-2009, University of Chicago)
Selected Editorial Boards
Editor-in-Chief, Quarterly Reviews of Biophysics, Cambridge University Press (2002-2007)
Selected Government Service
Scientific Advisor, Roadmap in Nanomedicine, NIH (2005-2011)
Vice-Chair, Biological Sciences Directorate Advisory Committee, NSF (2015-2017)
1986-88 Internship and Residency
Pediatric Medicine, Boston Children’s Hospital
1988-93 Clinical Fellowship
Pediatric Cardiology, Boston Children’s Hospital
1989-93 Research Fellow, Ion Channel Biophysics
Howard Hughes Medical Institute, Brandeis University (Christopher Miller)
Our research seeks to understand how ion channels operate in health and illness. Ion channels are membrane proteins in all cells that catalyze the selective passage of ions across membranes and, like enzymes, show exquisite specificity and tight regulation. As a class, ion channels orchestrate the electrical activity that allows operation of the heart, nervous system and skeletal muscles and are just as important in non-excitable cells like circulating T cells and sperm. Less sensational but equally important, ion channels mediate cellular fluid and electrolyte homeostasis. Remarkably, fundamental questions remain to be answered. How do ion channels open and close? What is their architecture? How do mutations produce cardiac arrhythmia, hypertension, seizures, or interfere with immune function? How do drugs act to produce beneficial outcomes (~20% of our current pharmacopeia targets ion channels) or to yield undesirable side effects? Our laboratory uses macroscopic and single molecule electrophysiology and spectroscopy, molecular genetics, high-throughput and structural methods to pursue five research directions.
(1) SUMOs—a pathway that controls the activity of ion channels at the cell surface. We identified an enzymatic pathway to operate at the cell surface and regulate the opening and closing of ion channels: post-translational modification with SUMO proteins. SUMOs were previously known to determine the activity of transcription factors in the nucleus. Enzymes for sumoylation and desumoylation were found to reside at the plasma membrane in all mammalian cells studied and the number of ion channels recognized to be modulated by the pathway is rapidly increasing. More recently, we recognized that hypoxia upregulates sumoylation of ion channels to produce cardiac arrythmia and neuronal pathology in the central nervous system.
(2) New genetic and high throughput methods for ion channels. (A) De novo development of peptide neurotoxins for “orphan” receptors. Among the most powerful tools in the arsenal for studies of the heart and nervous system, natural toxins are not selective -- we use phage display to generate de novo, high affinity specific peptides to study and modify the function of the channels in vivo. This has led to specific inhibitors and blockers (for example, of the proton channel that control sperm and neutrophil activity). (B) Other ongoing work allows studies of single ion channel complexes in living cells in real-time by total internal reflection microscopy and fluorescence energy transfer.
(3) Accessory Subunits—discovery, roles in health and disease, and structural basis for function. Ion channels are composed of pore-forming subunits and accessory subunits that determine where, when and how the pores function. Accessory subunits are the power behind the throne, determining the differences in how channels operate from tissue to tissue (and from cell to cell within the same tissue) allowing the heart to beat slowly and neurons to respond in milliseconds. In the heart, MinK (encoded by KCNE1) assembles with KCNQ1 (to form IKs channels) establishing the conductance, gating, regulation and anti-arrhythmic drug sensitivity of the mixed complexes. In mutant form, MinK is linked to cardiac arrhythmia and deafness. We found there is a family of genes encoding the MinK-related peptides (MiRPs) and have explored their roles helath and disease. Other accessory subunits we study include KChIPs, DPPs, 14-3-3 and KCTDs.
(4) The K2Ps—a family of potassium channels that produce background currents. Hodgkin and Huxley showed background potassium currents as central physiology but for 50 years their molecular nature was uncertain. We found K2P channels in yeast, worms, flies and mammals. The channels are novel in structure and function: they carry 2 pore-forming domains in each subunit. In humans, there are 15 KCNK genes for K2P channels and their roles in the heart and nervous system have emerged, for example, as targets of volatile anesthetics and unique forms of regulation in development and across tissues, for example, modification of ion selectivity via alternative initiation translation (ATI).
(5) Mechanism, diagnosis and treatment. We study disorders that are inherited and acquired (such as, sudden cardiac death, and sudden infant death syndrome, SIDS) to understand cause, provide diagnostic tools, develop therapeutic strategies and avoid untoward effects of medications. Thus, rare inherited mutations of MiRP1 are associated with the cardiac arrhythmia long QT syndrome (LQTS) as well as sudden death with a common polymorphism present in 1.6% of the general population that predisposes to drug-induced LQTS.
Sample Citations (Google Scholar References: https://tinyurl.com/ycnqnwqt)
Ketchum KA, Joiner WJ, Sellers AJ, Kaczmarek LK, & Goldstein SAN (1995) A new family of outwardly-rectifying potassium channel proteins with two pore domains in tandem. Nature 376:690-695.
Tai KK & Goldstein SAN (1998) The conduction pore of a cardiac potassium channel. Nature 391:605-608.
Abbott GW, et al. (2001) MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104(2):217-231.
Rajan S, Plant LD, Rabin ML, Butler MH, & Goldstein SAN (2005) Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121:37-47.
Plant LD, et al. (2006) A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. J Clin Invest 116:430-435.
Thomas, D., Plant, L.D., Wilkens, C.M., McCrossan, Z.A., and S.A.N. Goldstein. (2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron. 58:859-870.
Dementieva, I.S., Tereshko, V., McCrossan, Z.A., Solomaha, E., Araki, D., Xu, C., Grigorieff, N. and S.A.N. Goldstein. (2009). Pentameric assembly of potassium channel tetramerization domain-containing protein 5. J Mol Biol. 387:175-189.
Plant LD, Zuniga L, Araki D, Marks JD, & Goldstein SA (2012) SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons. Sci Signal 5(251):ra84.
Ruscic KJ, et al. (2013) IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits. Proc Natl Acad Sci U S A 110(7):E559-566.
Plant, L.D., Xiong, D., Dai, H. and S.A.N. Goldstein (2014). Individual IKs channels at the surface of mammalian cells contain two KCNE1 accessory subunits. Proc Natl Acad Sci. 111:E1438-E1446.
Zhao R., Dai, H., Mendelman, N., Cuello, L.G., Chill, J.H., and S.A.N. Goldstein. (2015) Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage display. Proc Natl Acad Sci U S A 112(50):E7013-7021.
Plant LD, Marks JD, & Goldstein SA (2016) SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons. eLife 5.
Xiong, D., Li, T., Dai, H., Arena, A.F., Plant, L.D., and Goldstein, S. A. N. (2017). SUMOylation determines the voltage required to activate cardiac IKs channels. Proc. Natl. Acad. Sci. (USA). 114 (32) E6686-E6694
Zhao R, Kennedy K, De Blas GA, Orta G, Pavarotti MA, Arias RJ, de la Vega-Beltrán JL, Li Q, Dai H, Perozo E, Mayorga LS, Darszon A, and Goldstein SAN. (2018). Role of human Hv1 channels in sperm capacitation and white blood cell respiratory burst established by a designed peptide inhibitor. Proc. Natl. Acad. Sci. (USA). Dec 11;115(50):E11847-E11856.
Zhao, R., Hui D., Mendelman, N., Chill, J.H., and Goldstein SAN (2020) Tethered peptide neurotoxins display two blocking mechanisms in the K+ channel pore as do their untethered analogues. Science Advances 6(10):eaaz3439
Plant, L.D., Xiong, D., Romero, J., Dai, H. and Goldstein, S.A.N. (2020) Hypoxia produces pro-arrhythmic late sodium current in cardiac myocytes by SUMOylation of NaV1.5 channels. Cell Reports 30(7):2225-36.e4
Dean and Chief Diversity Officer, Professor of Pediatrics and Physiology
Stritch School of Medicine, Loyola University Chicago 2017
Provost and Professor of Biochemistry
Brandeis University 2011
Chair of Pediatrics, Physician-in-Chief Comer Children's Hospital, Professor of Pediatrics
University of Chicago 2004
Professor, Pediatrics and Cellular and Molecular Physiology
Yale University 1993