The Research: Ion channel proteins act as gates controlling the flux of ions in and out of cells. Their function is essential for cellular electrical activity as well as electrolyte homeostasis. Tight regulation is a hallmark of ion channel function that is vital for fine tuning cellular excitability. Our laboratory recently identified a novel ion channel regulatory mechanism involving reversible peptide linkage (sumoylation) that had been previously known to mediate nuclear import/export and transcription. Covalent modification by a small ubiquitin-like modifier protein, SUMO-1, prevented the background potassium channel, K2P1, from passing potassium ions. The goal of this study is to investigate whether SUMO regulates volatge gated potassium channels. We present preliminary evidence for SUMO mediated inhibition of two voltage gated potassium channels, Kv2.1 and Kv4.3. Blockage of Kv2.1 has been implicated in eliciting glucose-dependent insulin secretion in pancreatic beta cells. Altered Kv4.3 expression has been demonstrated in heart failure. The proposed reasearch plan aims at expanding the understanding of sumoylation as a physiologically relevant regulatory mechanism with the help of various molecular, biochemical and electrophysiological methods. SUMO modulation of Kv4.3 and Kv2.1 will be studied in detail, including identification of modification sites, the effect of SUMO on currents generated by the aforementioned channels, and characterization of specific components of the modification pathway. Sumoylation of Kv2.1 will be studied in pancreatic beta cells where it is abundantly expressed. The candidate: Dr. Sindhu Rajan trained as an ion channel biologist during her Ph.D, which motivated her decision to pursue post-doctoral research in Dr. Steve Goldstein's laboratory. Her career goal is to do basic research, investigating ion channel function and dysfunction. This proposal is submitted to support her career development and help enable her to become an academically viable independent investigator. The environment: The candidate's mentor Dr. Steve Goldstein is a leading investigator in potassium channel research and ion channel diseases and his laboratory is rich in molecular biology, biochemistry and biophysical expertise. The Departments of Pediatrics, Neurobiology, Pharmacology and Physiology at the University of Chicago include an internationally recognized cadre of ion channel researchers.
|Liew, Chong Wee; Assmann, Anke; Templin, Andrew T et al. (2014) Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic ? cells. Proc Natl Acad Sci U S A 111:E2319-28|
|Eames, Stefani C; Kinkel, Mary D; Rajan, Sindhu et al. (2013) Transgenic zebrafish model of the C43G human insulin gene mutation. J Diabetes Investig 4:157-67|
|Rajan, Sindhu; Torres, Jacqueline; Thompson, Michael S et al. (2012) SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion. Am J Physiol Endocrinol Metab 302:E714-23|
|Musset, Boris; Smith, Susan M E; Rajan, Sindhu et al. (2010) Oligomerization of the voltage-gated proton channel. Channels (Austin) 4:260-5|
|Rajan, Sindhu; Eames, Stefani C; Park, Soo-Young et al. (2010) In vitro processing and secretion of mutant insulin proteins that cause permanent neonatal diabetes. Am J Physiol Endocrinol Metab 298:E403-10|
|Musset, Boris; Smith, Susan M E; Rajan, Sindhu et al. (2010) Zinc inhibition of monomeric and dimeric proton channels suggests cooperative gating. J Physiol 588:1435-49|