Faculty Listing > Faculty Detail
Steve A. N. Goldstein, MA, MD, PhD
Professor
Biophysics and Protein Dynamics, The Institute for Molecular Pediatric Sciences

Contact Information

(773) 702-6205 — Phone
(773) 702-4753 — Fax
sangoldstein@peds.bsd.uchicago.edu

Selected Publications

View a partial list of Steve A. N. Goldstein 's publications through the National Library of Medicine's PubMed online database

Research Interests

Our research is directed towards understanding how ion channels operate in health and illness. These integral membrane proteins catalyze the selective transfer of ions across membranes and, like enzymes, show exquisite specificity and tight regulation. As a class, ion channels orchestrate electrical signals that allow excitation of the heart, skeletal muscle and a circulating lymphocyte; less sensational but equally important, ion channels mediate cellular fluid and electrolyte homeostasis. Remarkably, some fundamental questions remain to be answered. How do they open and close? What is their architecture? How do inherited mutations produce cardiac arrhythmia, hypertension, seizures, or deafness? How do drugs act on ion channels to produce beneficial outcomes or harmful side-effects? The laboratory uses biophysical, genetic and biochemical methods to pursue four current research directions:

 (1) The normal role, mechanism for disease-association, and structure of the potassium channel accessory subunits. MinK (encoded by KCNE1) has just 129 amino acids and a single transmembrane domain and is active only after it assembles with pore-forming channel subunits. Nonetheless, MinK determines the essential character of key native channels. In the heart, MinK assembles with KCNQ1 to form IKs channels (thereby establishing conductance, gating, regulation and anti-arrhythmic drug sensitivity). In mutant form, MinK is associated with cardiac arrhythmia and deafness (due to changes in these same attributes); its role in the pancreas, T cells and gastrointestinal tract is still unknown. (Representative citations: Wang and Goldstein 1995. Neuron. 14:1303-9. Tai and Goldstein. 1998. Nature. 391:605-8. Chen et al. 2003. Neuron. 40:15-23.)

      For a decade it appeared that MinK was unique; recently, the laboratory identified a superfamily of genes encoding MinK-related peptides (MiRPs) and demonstrated roles for MiRP1 and MiRP2 in normal and disordered function of the heart and skeletal muscle, respectively. MiRP1 (encoded by KCNE2) has 123 residues and is most like MinK (although just 27% identical). It associates with the pore-forming subunit HERG to reconstitute the attributes of a current in the heart called IKr. Similarly, MiRP2 (encoded by KCNE3) is required with the pore-former Kv3.4 to assemble skeletal muscle channels and MiRP2 mutation is associated with dysfunction, in this case, periodic paralysis. (Representative citations: Abbott et al. 1999. Cell. 97:175-186. Abbott et al. 2001. Cell. 104:217-231. Abbott et al. 2006. FASEB J. 20:293-301). Other accessory subunits are also under study including KChIPs (Kim et al. 2004. Neuron. 41:513-519.)

 (2) Discovery, cloning and function of a new superfamily of potassium channels that produce "background leak", the K2Ps. Leaks have been known to be central to physiology for over 50 years but have been poorly understood (even their molecular nature was uncertain). The channels are found to be widely-expressed, numerous (17 separate gene families to date) and novel in structure as well as function: they bear 2 pore-forming domains in each subunit. Studies of isolates from yeast, mice and humans have begun to reveal their roles in the heart and nervous system, for example, as targets of volatile anesthetics. (Representative citations: Ketchum et al. 1995. Nature. 376:690-5. Goldstein et al. 1996. PNAS. 93:13256-61. Bockenhauer et al. 2001. Nature Neurosci. 4:486-491.)

     Recently, a novel mechanism to open and close these channels was discovered: post-translational modification with the protein called SUMO. SUMO was previously known to determine the activity of transcription factors in the nucleus and the enzymes for sumoylation and desumoylation at the plasma membrane shown to explain the silence of K2P1 channels. The utilization of this pathway to control other membrane proteins is predicted. (Representative citations: Rajan et al. 2005. Cell. 121: 37-47. Plant et al. 2005. Curr Opin Neurobiol. 15:26-333.)

 (3) Advancing the application of genetic tools to the function of ion channels (an approach heralded as "proteomics") and the association of ion channels with disease to enable diagnosis, therapy and prevention (gene-based medicine). The laboratory’s work in these methods has helped to identify the K2P superfamily and revealed the mechanism of operation of Killer RNA viruses that impact agriculture, commercial fermentation and fungal infections in immuno-compromised patients (a coupled toxin-immunity system acting via fungal two P domain channels). Most recently, random mutation and selective pressure has been applied to mammalian potassium channels expressed in yeast and bacterial cells and overproduction of material in functional form for structural studies. (Representative citations: Ahmed et al. 1999. Cell. 99:283-291. Sesti et al. 2001. Cell. 105:637-644. Sesti et al. 2003. Nature Neurosci. 6:353-361.)

 (4) Diagnosis and treatment strategies for diseases of ion channels, particularly, in children. Methods are now being applied to disorders of cardiac rhythm and sudden infant death syndrome seeking to understand cause, provide diagnostic tools and develop therapeutic strategies and avoid untoward effects of medications. Thus, rare inherited mutations of MiRP1 are associated with the arrhythmia long QT syndrome (LQTS) and sudden death while a common single nucleotide (SNP) polymorphism present in 1.6% of the general population predisposes to a prevalent and equally dangerous disorder: drug-induced LQTS and a SNP present in 11% of African Americans predisposes to sudden infant death syndrome (SIDS) (Representative citations: Sesti et al. 2000. PNAS. 10613-10618. Plant et al. 2006. J Clin Invest. 116: 430-435.)