Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty
KENNETH M. BLUMENTHAL, Ph.D.
Professor and Chairman
email: kblumen@buffalo.edu
Peptide Toxin Probes of Ion Channel Function and Architecture
Research in my laboratory is directed at understanding basic questions concerning structure-function relationships in ion channels. We are especially interested in using a variety of naturally-occurring toxins as probes of both ion transport and gating processes in these transmembrane macromolecules. To better understand the nature of these toxin binding sites, we have cloned and expressed synthetic genes which encode polypeptide modulators of the voltage-sensitive sodium channel and also of a peptidic blocker of the gastric chloride channel. By creating designed mutant forms of these toxins, and characterizing their functional properties and 3-dimensional structures, we hope to construct a picture of the channel region involved in binding. Complementary mutagenesis of channel products helps to define the structure of the channel itself, and this information is not accessible via other experimental approaches. Definition of toxin regions essential for this interaction will also allow us to design useful pharmacological agents directed at the target channel.
Selected Recent Publications
Page, B., Young, R., Iyer, V., Suzuki, G., Lis, M., Blumenthal, K.M., and Canty, J.M. (2007) “Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium,” Circ. Res. In press.
Coling, D., Ding, D., Lis, M., Young, R., Stofko, E., Blumenthal, K., and Salvi, R. (2007) “Proteomic analysis of cisplatin-induced cochlear damage: methods and early changes in protein expression,” Hearing Res., 226, 140-56. [PDF]
Smith, J.J., Cummins, T.R., Alphy, S., and Blumenthal, K.M. (2007) “Molecular interactions of the gating modifier toxin, ProTx-II, with Nav1.5: implied existence of a novel toxin binding site coupled to activation” J. Biol. Chem. 282, 12687-97, doi:10.1074/jbc.M610462200 [PDF]
Smith, J.J., and Blumenthal, K.M. (2007) “Site 3 sea anemone toxins: molecular probes of gating mechanisms in voltage-dependent sodium channels,” Toxicon, 49: 159-70 (invited review). [PDF]
Blumenthal, K.M., Priest, B.T., Smith, A., Smith, J.J., Warren, V.A., and Smith, M.M. (2006) “ProTx-I and ProTx-II: Gating modifiers of NaV and CaV channels,” Toxicon 49: 194-201. [PDF]
Kashlan, O.B., Maaroouf, A.B., Kussius, C., Denshaw, R.M., Blumenthal, K.M, and Kleyman, T.R. (2006) “Distinct structural elements in the first membrane-spanning domain of the epithelial sodium channel,” J. Biol. Chem. 281: 30455-62. doi:10.1074/jbc.M604615200
Lis, M., and Blumenthal, K. (2006) “A modified, dual reporter TOXCAT system for monitoring homodimerization of transmembrane segments of proteins,” Biochem. Biophys. Res. Commun. 339: 321-24.
Smith, J.J, Alphy, S., Seibert, A. L., and Blumenthal, K. M. (2005) Differential Phospholipid Binding by Site 3 and Site 4 Toxins: Implications for Structural Variability Between Voltage-Sensitive Sodium Channel Domains J. Biol. Chem. 280: 11127-11133; 10.1074/jbc.M412552200. [PDF]Seibert, A.L., Liu, J.S., Hanck, D.A., and Blumenthal, K.M. (2004) Role of Asn-16 and Ser-19 in Anthopleurin B Binding. Implications for the Electrostatic Nature of NaV Site 3, Biochemistry 43, 7082-89. (PDF)
Seibert, A.L., Liu, J., Hanck, D.A., and Blumenthal, K.M. (2003) Arg-14 Loop of Site 3 Anemone Toxins: Effects of Glycine Replacement on Toxin Affinity, Biochemistry 42, 14515-14521. (PDF)
Blumenthal, K.M., and Seibert, A.L. (2003) Voltage-gated Sodium Channel Toxins: Poisons, Probes and Future Promise, Cell Biochem. Biophys. 32, 215-238.