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

Yongping Chai, Yu-Fung Lin

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)897-915
Number of pages19
JournalPflugers Archiv European Journal of Physiology
Volume456
Issue number5
DOIs
StatePublished - Aug 2008

Fingerprint

Cyclic GMP-Dependent Protein Kinases
KATP Channels
Potassium Channels
Sulfonylurea Receptors
Cyclic GMP
Adenosine Triphosphate
Chemical activation
HEK293 Cells
Phosphodiesterase Inhibitors
Guanylate Cyclase
Clamping devices
Neuroblastoma
Potassium
Nitric Oxide
Protein Isoforms
Cells
Membranes
Kidney
Survival
Kir6.2 channel

Keywords

  • K channel
  • Nitric oxide
  • Patch clamp
  • Phosphorylation
  • Protein kinase G
  • Signal transduction
  • Single channel

ASJC Scopus subject areas

  • Physiology

Cite this

Dual regulation of the ATP-sensitive potassium channel by activation of cGMP-dependent protein kinase. / Chai, Yongping; Lin, Yu-Fung.

In: Pflugers Archiv European Journal of Physiology, Vol. 456, No. 5, 08.2008, p. 897-915.

Research output: Contribution to journalArticle

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