title: Protein kinase G dynamically modulates TASK1-mediated leak K+ currents in cholinergic neurons of the basal forebrain.
abstract: Leak K(+) conductance generated by TASK1/3 channels is crucial for neuronal excitability. However, endogenous modulators activating TASK channels in neurons remained unknown. We previously reported that in the presumed cholinergic neurons of the basal forebrain (BF), activation of NO-cGMP-PKG (protein kinase G) pathway enhanced the TASK1-like leak K(+) current (I-K(leak)). As 8-Br-cGMP enhanced the I-K(leak) mainly at pH 7.3 as if changing the I-K(leak) from TASK1-like to TASK3-like current, such an enhancement of the I-K(leak) would result either from an enhancement of hidden TASK3 component or from an acidic shift in the pH sensitivity profile of TASK1 component. In view of the report that protonation of TASK channel decreases its open probability, the present study was designed to examine whether the activation of PKG increases the conductance of TASK1 channels by reducing their binding affinity for H(+), i.e., by increasing K(d) for protonation, or not. We here demonstrate that PKG activation and inhibition respectively upregulate and downregulate TASK1 channels heterologously expressed in PKG-loaded HEK293 cells at physiological pH, by causing shifts in the K(d) in the acidic and basic directions, respectively. Such PKG modulations of TASK1 channels were largely abolished by mutating pH sensor H98. In the BF neurons that were identified to express ChAT and TASK1 channels, similar dynamic modulations of TASK1-like pH sensitivity of I-K(leak) were caused by PKG. It is strongly suggested that PKG activation and inhibition dynamically modulate TASK1 currents at physiological pH by bidirectionally changing K(d) values for protonation of the extracellular pH sensors of TASK1 channels in cholinergic BF neurons.
authors.affiliation: Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Makoto
authors.initials: M
authors.lastname: Okazawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Hirao
authors.forename: Hajime
authors.initials: H
authors.lastname: Sato
authors.forename: Haruka
authors.initials: H
authors.lastname: Abe
authors.forename: Kenji
authors.initials: K
authors.lastname: Takada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Funabiki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Youngnam
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002799:Cholinergic Fibers / Q000201:enzymology / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016548:Prosencephalon / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D017869:Cyclic GMP-Dependent Protein Kinases
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