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Dual regulation of the ATP-sensitive potassium channel by activation of cGMP-dependent protein kinase

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Abstract

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels couple cellular metabolic status to membrane electrical activity. In this study, we performed patch-clamp recordings to investigate how cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) regulates the function of KATP channels, using both transfected human SH-SY5Y neuroblastoma cells and embryonic kidney (HEK) 293 cells. In intact SH-SY5Y cells, the single-channel currents of Kir6.2/sulfonylurea receptor (SUR) 1 channels, a neuronal-type KATP isoform, were enhanced by zaprinast, a cGMP-specific phosphodiesterase inhibitor; this enhancement was abolished by inhibition of PKG, suggesting a stimulatory role of cGMP/PKG signaling in regulating the function of neuronal KATP channels. Similar effects of cGMP accumulation were confirmed in intact HEK293 cells expressing Kir6.2/SUR1 channels. In contrast, direct application of purified PKG suppressed rather than activated Kir6.2/SUR1 channels in excised, inside-out patches, while tetrameric Kir6.2LRKR368/369/370/371AAAA channels expressed without the SUR subunit were not modulated by zaprinast or purified PKG. Lastly, reconstitution of the soluble guanylyl cyclase/cGMP/PKG signaling pathway by generation of nitric oxide led to Kir6.2/SUR1 channel activation in both cell types. Taken together, here, we report novel findings that PKG exerts dual functional regulation of neuronal KATP channels in a SUR subunit-dependent manner, which may provide new means of therapeutic intervention for manipulating neuronal excitability and/or survival.

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Acknowledgments

We thank Dr. Susumu Seino (Kobe University, Chuo-ku, Japan) and Dr. Joseph Bryan (Baylor College of Medicine, Houston, TX) for the kind gifts of cDNA clones of hamster SUR1, rat SUR2A, and mouse Kir6.2. The cDNA of Kir6.2FL4A was a kind gift from Dr. Blanche Schwappach (University of Heidelberg, Heidelberg, Germany). The single-channel analysis program Intrv5 was generously provided by Drs. Barry Pallotta (University of North Carolina, Chapel Hill) and Janet Fisher (University of South Carolina, Columbia, SC). This study was supported by UC Davis seed fund (Y.F.L.), UC Davis Health System Research Award (Y.F.L.), and American Heart Association Scientist Development Grant (Y.F.L.) and was conducted in a facility constructed with support from Research Facilities Improvement Program Grant number C06 RR-12088-01 from the National Center for Research Resources, National Institutes of Health.

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  1. Department of Physiology and Membrane Biology, University of California, Rm. 4144, Tupper Hall, One Shields Avenue, Davis, CA, 95616, USA

    Yongping Chai & Yu-Fung Lin

  2. Department of Anesthesiology, University of California, Davis, CA, 95616, USA

    Yu-Fung Lin

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Chai, Y., Lin, YF. Dual regulation of the ATP-sensitive potassium channel by activation of cGMP-dependent protein kinase. Pflugers Arch - Eur J Physiol 456, 897–915 (2008). https://doi.org/10.1007/s00424-008-0447-z

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