Volatile anesthetic represent some of the most clinically important drugs in currents use. They are used to produce reversible interruption of consciousness and thereby induce insensitivity to pain and other sensory stimulation. Clearly, anesthetic must interfere with the proper function of precesses fundamental to the operation of synapses involved in perception. Thus, the study of their action has great promise for elucidating important neurophysiologic functions. Another striking aspects of anesthetic action is that, unlike other drugs, anesthetics display a remarkable constancy of effect and potency over enormous evolutionary span. This fact suggests that the site of action of anesthetics has been highly conserved. We have made use of this observation by studying the effect of anesthetics in the well defined nervous system of the mollusc, Aplysia californica. As a results of our initial experiments, we have found that anesthetics silence certain spontaneously firing neurons in Aplysia by a mechanism that involves activation of a voltage-independent potassium channel. We have identified this channel as the S-K+ channel by several criteria. Currently, we are investigating the mechanism by which this activation occurs. This characterization will lead to isolation of the ion channel by molecular cloning that in turn will allow us to search for related ions channels in the far more complex mammalian central nervous system. This propose research is important from three perspectives: (1) it will help elucidate the molecular basis of general anesthetic action; (2) it will lead to a greater understanding of the operation of synapses in the CNS; (3) it will help in the development of more specific anesthetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29GM051372-01
Application #
2189853
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kindler, Christoph H; Paul, Matthias; Zou, Hilary et al. (2003) Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5). J Pharmacol Exp Ther 306:84-92
Gray, A T; Zhao, B B; Kindler, C H et al. (2000) Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5. Anesthesiology 92:1722-30
Kindler, C H; Verotta, D; Gray, A T et al. (2000) Additive inhibition of nicotinic acetylcholine receptors by corticosteroids and the neuromuscular blocking drug vecuronium. Anesthesiology 92:821-32
Kindler, C H; Pietruck, C; Yost, C S et al. (2000) Localization of the tandem pore domain K+ channel TASK-1 in the rat central nervous system. Brain Res Mol Brain Res 80:99-108
Chavez, R A; Gray, A T; Zhao, B B et al. (1999) TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family. J Biol Chem 274:7887-92
Gray, A T; Kindler, C H; Sampson, E R et al. (1999) Assignment of KCNK6 encoding the human weak inward rectifier potassium channel TWIK-2 to chromosome band 19q13.1 by radiation hybrid mapping. Cytogenet Cell Genet 84:190-1
Yost, C S (1999) Potassium channels: basic aspects, functional roles, and medical significance. Anesthesiology 90:1186-203
Kindler, C H; Yost, C S; Gray, A T (1999) Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem. Anesthesiology 90:1092-102
Yost, C S; Hampson, A J; Leonoudakis, D et al. (1998) Oleamide potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor activity but does not alter minimum alveolar anesthetic concentration. Anesth Analg 86:1294-300
Leonoudakis, D; Gray, A T; Winegar, B D et al. (1998) An open rectifier potassium channel with two pore domains in tandem cloned from rat cerebellum. J Neurosci 18:868-77

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