Voltage-dependent K+ channels regulate the excitability of neurons and serve as receptors for a variety of synthetic drugs and natural toxins. Recently, cDNAs encoding rat brain K+ channels have been isolated. When expressed in Xenopus oocytes different K+ channel clones have different pharmacological profiles, but little is known about the mechanisms of action of pharmacological agents in brain K+ channels or their binding sites on the channel proteins. We propose to use a combination of electrophysiological and recombinant DNA methods to identify and probe regions of the K+ channel primary structure which interact with toxins and drugs. Binding sites will be probed by site-directed mutagenesis and mechanisms of action will be investigated by voltage-clamp electro- physiology in the Xenopus oocyte expression system. Expression of pure channel isoforms in oocytes provides a unique opportunity for studying drug mechanisms unencumbered by the usual complexities arising from the presence of heterogenous K+ channel subtypes in excitable cells. The results of this study should provide insight into K+ channel surface topography, help to elucidate the structural basis for drug and toxin specificity, and guide the development of therapeutic agents targeted against K+ channels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS029473-01A1
Application #
3416307
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1991-09-30
Project End
1995-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Klemic, K G; Kirsch, G E; Jones, S W (2001) U-type inactivation of Kv3.1 and Shaker potassium channels. Biophys J 81:814-26
Kirsch, G E (1999) Ion channel defects in cardiac arrhythmia. J Membr Biol 170:181-90
Klemic, K G; Shieh, C C; Kirsch, G E et al. (1998) Inactivation of Kv2.1 potassium channels. Biophys J 74:1779-89
Dumaine, R; Kirsch, G E (1998) Mechanism of lidocaine block of late current in long Q-T mutant Na+ channels. Am J Physiol 274:H477-87
Kramer, J W; Post, M A; Brown, A M et al. (1998) Modulation of potassium channel gating by coexpression of Kv2.1 with regulatory Kv5.1 or Kv6.1 alpha-subunits. Am J Physiol 274:C1501-10
Chen, S; Hartmann, H A; Kirsch, G E (1997) Cysteine mapping in the ion selectivity and toxin binding region of the cardiac Na+ channel pore. J Membr Biol 155:11-25
Pascual, J M; Shieh, C C; Kirsch, G E et al. (1997) Contribution of the NH2 terminus of Kv2.1 to channel activation. Am J Physiol 273:C1849-58
Shieh, C C; Klemic, K G; Kirsch, G E (1997) Role of transmembrane segment S5 on gating of voltage-dependent K+ channels. J Gen Physiol 109:767-78
Post, M A; Kirsch, G E; Brown, A M (1996) Kv2.1 and electrically silent Kv6.1 potassium channel subunits combine and express a novel current. FEBS Lett 399:177-82
Dumaine, R; Wang, Q; Keating, M T et al. (1996) Multiple mechanisms of Na+ channel--linked long-QT syndrome. Circ Res 78:916-24

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