Protein kinase G dynamically modulates TASK1-mediated leak K+ currents in cholinergic neurons of the basal forebrain.
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.
Toyoda
Hiroki
H
Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
Saito
Mitsuru
M
Okazawa
Makoto
M
Hirao
Keiko
K
Sato
Hajime
H
Abe
Haruka
H
Takada
Kenji
K
Funabiki
Kazuo
K
Takada
Masahiko
M
Kaneko
Takeshi
T
Kang
Youngnam
Y
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
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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