A complete understanding of the cellular and molecular basis of the anesthetized state produced by volatile anesthestics remains elusive. Ion channel proteins provide the most likely molecular targets for these agents. Many studies have provided evidence for the involvement of GABAergic and glutamatergic receptor systems in mediating the action of volatile anesthetics. An additional type of ionic current, background potassium currents(also known as resting or baseline K+ currents) have recently been identified as plausible sites for volatile anesthetic action. This grant is a continuation of studies begun six years ago to elucidate the role of background K+ currents in normal physiology and in the anesthetized state. A new structural class of K+ channels with two pore-forming sequences in tandem are responsible for background K+ currents. We have cloned members of this family, demonstrated their presence in the central nervous system and studied their activation by volatile anesthetics at concentrations overlapping the clinical range. Other investigators have recorded the activity of background K+ channels in vivo and demonstrated inhibitory effects on neuronal systems that are enhanced by volatile anesthetics.
The aims of this grant are threefold: (1) to characterize the function and anesthetic sensitivity of the remaining undiscovered members of this structural class of ion channels; (2) to study at the cellular level the tissue distribution of tandem pore K+ channels to gain insight into their normal physiologic function; (3) to identify the molecular domains responsible for volatile anesthetic action. With these experiments we expect that a more complete understanding of background K+ channels will emerge and their role in mediating the anesthetic state clarified.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058149-05
Application #
6525464
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1998-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$268,450
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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