Faculty Profile: Goldstein, Steven
|Faculty Information||Lab Information (Packet Type, Course Title, & Department)||Location|
CHANNELS & DISEASE
Department: Physiology and Biophysics
Our research asks 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 they are also 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 they open and close? What is their architecture? How do mutations produce cardiac arrhythmia, seizures, or interfere with immune function? How do drugs 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 areas.
(1) SUMOs—We identified post-translational modification with SUMO proteins to operate at the cell surface and regulate the opening and closing of ion channels. 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 and the number of ion channels recognized to be modulated by the pathway is rapidly increasing. More recently, we recognized that hypoxia as seen with myocardial infarction and stroke upregulates the sumoylation of ion channels to produce cardiac arrhythmia and neuronal pathology in the central nervous system, respectively.
(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 controls 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 forms, 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 health 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) The mechanism, diagnosis, and treatment of disease. We study disorders that are inherited and acquired (such as, sudden cardiac death, and sudden infant death syndrome, SIDS) to understand the 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.
Google Scholar References: https://tinyurl.com/ycnqnwqt
Ketchum KA, et al. (1995) A new family of outwardly-rectifying potassium channel proteins with two pore domains in tandem. Nature 376:690-5.
Abbott GW, et al. (2001) MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with perio
Requirements to Participate
Complete first two years of college or prior laboratory experience. 1 year Commitment.
Faculty Means of Evaluation
Attendance: 20Pts (working assigned hours, being on time)
Lab Work: 40Pts (quality, accuracy, integrated.synthesis of information and safety)
Communication: 20Pts (Written/Oral reports, questions, and discussion with the mentor)
Lab citizenship: 20Pts (organization, clean up and follow through)