Although it has been known for more than 150 years that volatile anesthetics produce central nervous system (CNS) depression in numerous species, the basic mechanisms underlying anesthetic action are not yet understood. We hypothesize that volatile anesthetics induce neuronal inhibition primarily by activating a discrete class of potassium (K+) channels responsible for background currents (also known as baseline or leak currents). We have shown that in neurons of the mollusc Aplysia californica, volatile anesthetics increase the open probability of an outwardly rectifying background K+ channel (S-K channel), resulting in neuronal hyperpolarization and silencing of spontaneous action potentials. A recently discovered class of K+ channels, distinguished by having two putative pore-forming sequences tandemly arrayed within their primary amino acid sequence, appears to mediate background currents. We found that the function of the prototypic member of this family, a yeast outwardly rectifying background channel (TOK1) is potentiated by volatile anesthetics. TOK1 potentiation obeys the rank order of clinical potency halothane greater than isoflurane greater than desflurane), overlaps the clinical range, does not occur with non- anesthetics and is stereospecific [S(+) greater than R(-)-isoflurane]. We also have preliminary evidence for the presence of volatile anesthetic-stimulated baseline K+ channels in mammalian brain (rat cerebellar granule cells). We now propose the continuation of these studies by cloning and expressing new members of the tandem pore K+ channel family for studies of their sensitivity to volatile anesthetics. The proposed studies are important from three perspectives: 1) they have the potential for elucidating a molecular mechanism of volatile anesthetic action; 2) they will lead to a greater understanding of the role of background channels in CNS activity; 3) they may provide targets for the development of more specific anesthetic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM058149-01
Application #
2686327
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1998-09-30
Project End
2001-08-31
Budget Start
1998-09-30
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
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
Chae, Yun Jeong; Zhang, Jianan; Au, Paul et al. (2010) Discrete change in volatile anesthetic sensitivity in mice with inactivated tandem pore potassium ion channel TRESK. Anesthesiology 113:1326-37
Yoo, SieHyeon; Liu, Jia; Sabbadini, Marta et al. (2009) Regional expression of the anesthetic-activated potassium channel TRESK in the rat nervous system. Neurosci Lett 465:79-84
Kopp Lugli, Andrea; Yost, Charles Spencer; Kindler, Christoph H (2009) Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia. Eur J Anaesthesiol 26:807-20
Yost, C Spencer; Oh, Irene; Eger 2nd, Edmond I et al. (2008) Knockout of the gene encoding the K(2P) channel KCNK7 does not alter volatile anesthetic sensitivity. Behav Brain Res 193:192-6
Cotten, Joseph F; Keshavaprasad, Bharat; Laster, Michael J et al. (2006) The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration. Anesth Analg 102:779-85
Kindler, Christoph H; Yost, C Spencer (2005) Two-pore domain potassium channels: new sites of local anesthetic action and toxicity. Reg Anesth Pain Med 30:260-74
Liu, Canhui; Cotten, Joseph F; Schuyler, Jennifer A et al. (2005) Protective effects of TASK-3 (KCNK9) and related 2P K channels during cellular stress. Brain Res 1031:164-73
Keshavaprasad, Bharat; Liu, Canhui; Au, John D et al. (2005) Species-specific differences in response to anesthetics and other modulators by the K2P channel TRESK. Anesth Analg 101:1042-9, table of contents
Paul, Matthias; Callahan, Robert; Au, John et al. (2005) Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors. Anesth Analg 101:715-21, table of contents
Callahan, Robert J; Au, John D; Paul, Matthias et al. (2004) Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects. Anesth Analg 98:653-9, table of contents

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