Steven S. King
Steven C. King, Ph.D. (Harvard, 1990)
Research InterestsMy academic interests lie in the study of structure-function relationships as they relate to biological transport processes. My laboratory engages in research aimed at determining how the structure of a (Cation/Substrate)-cotransport protein determines its function. The seemingly endless variety of cotransport proteins that can be found in plasma membranes throughout nature speaks to the key role that these molecules play in regulating the composition of both intracellular spaces (e.g., amino acid uptake), and extracellular spaces (e.g., neurotransmitter uptake). Our recent work has focused on GABA transporters. GABA (g-aminobutyric acid) is a simple amino acid that serves an intracellular role, linking nitrogen metabolism to carbohydrate metabolism, plus an extracellular role as the major inhibitory neurotransmitter in the mammalian nervous system. Thus from a basic science perspective, broad-based structure-function studies across species will reveal molecular details of the specializations that allow transporters to regulate the availability of GABA to support both intracellular and extracellular activities. From a more clinical perspective, a detailed picture of GABA transporter structure and function will reveal unrecognized points of vulnerability that can be targeted by new agents designed to inhibit transport. GABA transport inhibitors facilitate GABAergic transmission and exhibit clinically useful anticonvulsant activity. Novel GABA transport inhibitors may be anticipated to complement the sedative and anxiolytic properties of barbiturates and benzodiazepines, which facilitate GABAergic transmission by a different mechanism. Our overall approach to meeting these goals involves broad-based utilization of cloned transporters from bacteria to mammals together with application of methodologies ranging from transport physiology to protein chemistry and molecular biology.
Selected PublicationsZhang W, Campbell HA, King SC, Dowhan W. Phospholipids as determinants of membrane protein topology. Phosphatidylethanolamine is required for the proper topological organization of the gamma-aminobutyric acid permease (GabP) of Escherichia coli.J Biol Chem. 2005;280(28):26032-8. Epub 2005 May 12.
King SC. The "Transport Specificity Ratio": a structure-function tool to search the protein fold for loci that control transition state stability in membrane transport catalysis.BMC Biochem. 2004;5:16.
King SC, Brown-Istvan L. Use of the transport specificity ratio and cysteine-scanning mutagenesis to detect multiple substrate specificity determinants in the consensus amphipathic region of the Escherichia coli GABA (gamma-aminobutyric acid) transporter encoded by gabP. Biochem J. 2003 Dec 15;376(Pt 3):633-44.
King SC, Hu LA, Pugh A. Induction of substrate specificity shifts by placement of alanine insertions within the consensus amphipathic region of the Escherichia coli GABA (gamma-aminobutyric acid) transporter encoded by gabP. Biochem J. 2003;376(Pt 3):645-53.
Hu LA, King SC. Identification of the amine-polyamine-choline transporter superfamily 'consensus amphipathic region' as the target for inactivation of the Escherichia coli GABA transporter GabP by thiol modification reagents. Role of Cys-300 in restoring thiol sensitivity to Gabp lacking Cys. Biochem J. 1999;339 ( Pt 3):649-55.