Guanosine promotes the up-regulation of inward rectifier potassium current mediated by Kir4.1 in cultured rat cortical astrocytes.
Guanosine (Guo) is an endogenous neuroprotective molecule of the CNS, which has various acute and long-term effects on both neurones and astroglial cells. Whether Guo also modulates the activity/expression of ion channels involved in homeostatic control of extracellular potassium by the astrocytic syncytium is still unknown. Here we provide electrophysiological evidence that chronic exposure (48 h) to Guo (500 microm) promotes the functional expression of an inward rectifier K+ (Kir) conductance in primary cultured rat cortical astrocytes. Molecular screening indicated that Guo promotes the up-regulation of the Kir4.1 channel, the major component of the Kir current in astroglia in vivo. Furthermore, the properties of astrocytic Kir current overlapped those of the recombinant Kir4.1 channel expressed in a heterologous system, strongly suggesting that the Guo-induced Kir conductance is mainly gated by Kir4.1. In contrast, the expression levels of two other Kir channel proteins were either unchanged (Kir2.1) or decreased (Kir5.1). Finally, we showed that inhibition of translational process, but not depression of transcription, prevents the Guo-induced up-regulation of Kir4.1, indicating that this nucleoside acts through de novo protein synthesis. Because accumulating data indicate that down-regulation of astroglial Kir current contributes to the pathogenesis of neurodegenerative diseases associated with dysregulation of extracellular K+ homeostasis, these results support the notion that Guo might be a molecule of therapeutic interest for counteracting the detrimental effect of K+-buffering impairment of the astroglial syncytium that occurs in pathological conditions.
Benfenati
Valentina
V
Department of Human and General Physiology, University of Bologna, Bologna, Italy.
Caprini
Marco
M
Nobile
Mario
M
Rapisarda
Carmela
C
Ferroni
Stefano
S
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004594:Electrophysiology; D006151:Guanosine / Q000494:pharmacology*; D006706:Homeostasis; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D018696:Neuroprotective Agents; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D000098854:Kcnj10 Channel
D018076:DNA, Complementary; D000098854:Kcnj10 Channel; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D024661:Potassium Channels, Inwardly Rectifying; D006151:Guanosine