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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Bradykinin inhibits the transient outward K⁺ current in mouse Schwann cells via the cAMP/PKA pathway

Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

Submitted 13 January 2009 ; accepted in final form 27 March 2009

Bradykinin (BK) is an endogenous peptide with diverse biological actions and is considered to be an important mediator of the inflammatory response in both the peripheral and the central nervous systems. BK has attracted recent interest as a potential mediator of K⁺ conductance, Cl^– channels, and Ca²⁺-activated K⁺ channels. However, few reports have associated BK with the voltage-gated K⁺ current. In this study, we demonstrated that BK suppressed the transient outward potassium current (I_A) in mouse Schwann cells using whole cell recording techniques. At a concentration of 0.1 µM to 5 µM, BK reversibly inhibited I_A in a dose-dependent manner with the modulation of steady-state activation and inactivation properties. The effect of BK on I_A current was abolished after preincubation with a B₂ receptor antagonist but could not be eliminated by B₁ receptor antagonist. Intracellular application of GTP-S induced an irreversible decrease in I_A, and the inhibition of G_s using NF449 provoked a gradual augmentation in I_A and eliminated the BK-induced effect on I_A, while the G_i/_o antagonist NF023 did not. The application of forskolin or dibutyryl-cAMP mimicked the inhibitory effect of BK on I_A and abolished the BK-induced effect on I_A. H-89, an inhibitor of PKA, augmented I_A amplitude and completely eliminated the BK-induced inhibitory effect on I_A. In contrast, activation of PKC by PMA augmented I_A amplitude. A cAMP assay revealed that BK significantly increased intracellular cAMP level. It is therefore concluded that BK inhibits the I_A current in Schwann cells by cAMP/PKA-dependent pathways via activation of the B₂ receptor.

inactivating A-type outward K⁺ current; B₁/B₂ receptor; adenosine 3',5'-cyclic monophosphate/protein kinase A