This proposal concerns the regulation of ion-channel function by G-protein-coupled receptor (GPCR) signaling to membrane lipids. It focuses on the hypothesis that the function of many ion channels depends on the concentration of one rare phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane. The kinetics of signaling steps from M1 muscarinic receptors to phospholipase C will be measured to test the hypothesis that they are fast, perhaps reflecting a preformed signaling complex. The kinetics of the metabolic steps that deplete and replenish PIP2 will be measured to understand the cellular sources and dynamics of PIP2. All results will be fitted with a comprehensive kinetic model to provide additional information on the mechanisms of the signaling cascade. The ability of PIP2 concentration changes and muscarinic signaling to modulate function of KCNQ channels, several voltage-gated K+ channels (Kv channels), and voltage-gated Ca2+ channels (Cav channels) will be studied. The ability of arachidonic acid to modulate KCNQ and Cav channels will be analyzed. Physiological mechanisms for arachidonic acid production initiated by GPCR inputs will be defined. The methods will include patch-clamp electrophysiology, fluorescence resonance energy transfer, dynamic targeting of enzymes to cellular membranes, confocal microscopy, and chemical analysis. Most of the studies will be done on cell lines but a small number will be done in nerve cells of rodents to demonstrate the relevance to mammalian physiology. This work lays the basis for understanding hormonal control of mental state and the actions of many drugs of biological psychiatry. Many drugs of abuse and drugs of psychiatry act on the signaling systems studied here. The involuntary nervous system talks to its targets by the signaling mechanisms elucidated here.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Stewart, Randall R
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University of Washington
Schools of Medicine
United States
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Hille, Bertil; Dickson, Eamonn J; Kruse, Martin et al. (2015) Phosphoinositides regulate ion channels. Biochim Biophys Acta 1851:844-56
Hille, Bertil; Dickson, Eamonn; Kruse, Martin et al. (2014) Dynamic metabolic control of an ion channel. Prog Mol Biol Transl Sci 123:219-47
Dickson, Eamonn J; Falkenburger, Bjorn H; Hille, Bertil (2013) Quantitative properties and receptor reserve of the IP(3) and calcium branch of G(q)-coupled receptor signaling. J Gen Physiol 141:521-35
Falkenburger, Bjorn H; Dickson, Eamonn J; Hille, Bertil (2013) Quantitative properties and receptor reserve of the DAG and PKC branch of G(q)-coupled receptor signaling. J Gen Physiol 141:537-55
Kruse, Martin; Hille, Bertil (2013) The phosphoinositide sensitivity of the K(v) channel family. Channels (Austin) 7:530-6
Kim, Mean-Hwan; Seo, Jong Bae; Burnett, Lindsey A et al. (2013) Characterization of store-operated Ca2+ channels in pancreatic duct epithelia. Cell Calcium 54:266-75
Suh, Byung-Chang; Kim, Dong-Il; Falkenburger, Bjorn H et al. (2012) Membrane-localized ýý-subunits alter the PIP2 regulation of high-voltage activated Ca2+ channels. Proc Natl Acad Sci U S A 109:3161-6
Falkenburger, Bjorn H; Jensen, Jill B; Hille, Bertil (2010) Kinetics of PIP2 metabolism and KCNQ2/3 channel regulation studied with a voltage-sensitive phosphatase in living cells. J Gen Physiol 135:99-114
Falkenburger, Björn H; Jensen, Jill B; Hille, Bertil (2010) Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells. J Gen Physiol 135:81-97
Suh, Byung-Chang; Leal, Karina; Hille, Bertil (2010) Modulation of high-voltage activated Ca(2+) channels by membrane phosphatidylinositol 4,5-bisphosphate. Neuron 67:224-38

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