PMID:18231807
| Citation |
Chai, Y and Lin, YF (2008) Dual regulation of the ATP-sensitive potassium channel by activation of cGMP-dependent protein kinase. Pflugers Arch. 456:897-915 |
|---|---|
| Abstract |
Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) 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 K(ATP) 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 K(ATP) 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 K(ATP) 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 K(ATP) channels in a SUR subunit-dependent manner, which may provide new means of therapeutic intervention for manipulating neuronal excitability and/or survival. |
| Links |
PubMed Online version:10.1007/s00424-008-0447-z |
| Keywords |
Adenosine Triphosphate/metabolism; Animals; Carbazoles/metabolism; Cell Line; Cyclic GMP-Dependent Protein Kinases/metabolism; Enzyme Inhibitors/metabolism; Humans; KATP Channels/metabolism; Neurons/cytology; Neurons/metabolism; Nitric Oxide/metabolism; Nitric Oxide Donors/metabolism; Nitroso Compounds/metabolism; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying/metabolism; Purinones/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Signal Transduction/physiology |
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