β‐Adrenergic Modulation of Glial Inwardly Rectifying Potassium Channels

Abstract: Cultured spinal cord astrocytes (2–13 days in vitro) express several different potassium current types, including delayed rectifier, transient A‐type, and inward rectifier (K ir ) K + currents. Of these, K ir 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 K ir currents by β‐adrenergic receptor activation. The selective β‐adrenergic agonist isoproterenol (1–100 µ M ) and epinephrine (1–100 µ M ) each reduced peak K ir current amplitudes to 52.7 ± 12.5 and 63.6 ± 7.0%, respectively, at 100 µ M . Forskolin ( K D of ∼25 µ M ), an activator of adenylate cyclase (AC), and dibutyryl‐cyclic AMP (1 m M ), 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 K ir currents. By contrast, 1,9‐dideoxyforskolin (1–50 µ M ), a forskolin analogue that does not activate AC, did not affect K ir currents, indicating that AC activity is a required element for K ir 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 K ir current reduction by β‐adrenergic agonists. These results indicate that β‐adrenergic receptor ligands can modulate K ir 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 K ir currents and thereby may affect glial K + “spatial buffering” in the CNS.