Beta-adrenergic modulation of glial inwardly rectifying potassium channels.
Cultured spinal cord astrocytes (2-13 days in vitro) express several different potassium current types, including delayed rectifier, transient A-type, and inward rectifier (Kir) K+ currents. Of these, Kir is believed to be of critical importance in the modulation of extracellular [K+] in the CNS. Using the whole-cell patch-clamp technique, we analyzed modulation of Kir currents by beta-adrenergic receptor activation. The selective beta-adrenergic agonist isoproterenol (1-100 microM) and epinephrine (1-100 microM) each reduced peak Kir current amplitudes to 52.7 +/- 12.5 and 63.6 +/- 7.0%, respectively, at 100 microM. Forskolin (KD of approximately 25 microM), an activator of adenylate cyclase (AC), and dibutyryl-cyclic AMP (1 mM), a membrane-permeable analogue of cyclic AMP (cAMP), were each used to increase [cAMP]i, the product of AC, and resulted in similar reductions of Kir currents. By contrast, 1,9-dideoxyforskolin (1-50 microM), a forskolin analogue that does not activate AC, did not affect Kir currents, indicating that AC activity is a required element for Kir modulation. Three inhibitors of PKA--Rp-adenosine 3',5'-cyclic monophosphothioate, H-7, and adenosine 3',5'-cyclic monophosphate-dependent protein kinase inhibitor--failed to inhibit Kir current reduction by beta-adrenergic agonists. These results indicate that beta-adrenergic receptor ligands can modulate Kir currents and suggest that this modulation involves activation of AC but not protein kinase A. Such modulation may provide a mechanism by which neurons can modulate glial Kir currents and thereby may affect glial K+ "spatial buffering" in the CNS.
Roy
M L
ML
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.
Sontheimer
H
H
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004594:Electrophysiology; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009457:Neuroglia / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D004837:Epinephrine