Abstract

ATP is a ubiquitous intracellular metabolite which serves both as a store for chemical energy and as a second messenger. A class of potassium channels which are inhibited by intracellular ATP has been detected in a variety of tissues. K-ATP channels have been implicated in diverse metabolic processes as well as pathological conditions such as diabetes, ischemia and hypoxia, and epilepsy. A PCR-based cloning strategy has identified many novel potassium channel clones; expression of one clone isolated from rat heart resulted in functional K-ATP channels. The expressed channels show inward rectification, are inhibited by intracellular ATP or AMP-PNP, are reactivated by nucleotide diphosphates following rundown, and are sensitive to potassium channel openers such as pinacidil. In contrast to native K-ATP channels, the cloned channels are not affected by sulfonylureas such as glyburide. A highly related, but distinct clone has also been isolated from pancreatic islet cells. To understand the mechanisms which regulate K-ATP channels, we will: 1. Determine the domains and specific residues which comprise the nucleotide binding sites of cloned K-ATP channels. 2. Determine the relationship between sulfonylurea receptors and K-ATP channels. 3. Determine whether cloned K-ATP channels are sensitive to modulation by G-proteins.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS028504-05
Application #
2266981
Study Section
Physiology Study Section (PHY)
Project Start
1991-02-01
Project End
1999-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Type
Organized Research Units
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

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Whyte, D B; Lawson, M A; Belsham, D D et al. (1995) A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons. Mol Endocrinol 9:467-77
Lagrutta, A; Shen, K Z; North, R A et al. (1994) Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel. J Biol Chem 269:20347-51
Perez, G; Lagrutta, A; Adelman, J P et al. (1994) Reconstitution of expressed KCa channels from Xenopus oocytes to lipid bilayers. Biophys J 66:1022-7
White, S A; Bond, C T; Francis, R C et al. (1994) A second gene for gonadotropin-releasing hormone: cDNA and expression pattern in the brain. Proc Natl Acad Sci U S A 91:1423-7
Varnum, M D; Busch, A E; Bond, C T et al. (1993) The min K channel underlies the cardiac potassium current IKs and mediates species-specific responses to protein kinase C. Proc Natl Acad Sci U S A 90:11528-32
Yakel, J L; Lagrutta, A; Adelman, J P et al. (1993) Single amino acid substitution affects desensitization of the 5-hydroxytryptamine type 3 receptor expressed in Xenopus oocytes. Proc Natl Acad Sci U S A 90:5030-3
Busch, A E; Varnum, M; Adelman, J P et al. (1992) Hypotonic solution increases the slowly activating potassium current IsK expressed in xenopus oocytes. Biochem Biophys Res Commun 184:804-10
Busch, A E; Kavanaugh, M P; Varnum, M D et al. (1992) Regulation by second messengers of the slowly activating, voltage-dependent potassium current expressed in Xenopus oocytes. J Physiol 450:491-502
Busch, A E; Varnum, M D; North, R A et al. (1992) An amino acid mutation in a potassium channel that prevents inhibition by protein kinase C. Science 255:1705-7

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