PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons.

Paula Rivas-Ramírez,Antonio Reboreda,Lola Rueda-Ruzafa,J. Antonio Lamas,Salvador Herrera-Pérez

doi:10.3390/ijms21020389

Paula Rivas-Ramírez, Antonio Reboreda + Show 3 more

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https://doi.org/10.3390/ijms21020389

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Abstract

Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca2+-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the “Tandem of pore-domains in a Weakly Inward rectifying K+ channel (TWIK)-related channels” (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.

Highlights

Bradykinin (BK) is released during tissue damage, it is one of the main mediators of inflammation and is able to activate and sensitize the nociceptor neurons mainly through the activation of B2 receptors (B2Rs) [1,2,3]
We have recently reported that the inhibition of TREK-2 channels by muscarinic agonists in mouse SCG (mSCG) neurons greatly depends on PIP2 depletion [25]
The TREK subfamily has been implicated in the transduction of mechanical, chemical, and thermal stimuli [60,61], and related to pain transduction, as it is well expressed in dorsal root ganglia (DRG) small neurons and in trigeminal ganglia neurons [62,63,64,65]

Summary

Introduction

Bradykinin (BK) is released during tissue damage, it is one of the main mediators of inflammation and is able to activate and sensitize the nociceptor neurons mainly through the activation of B2 receptors (B2Rs) [1,2,3]. The presence of bradykinin receptors (BRs) in motor neurons of the sympathetic superior cervical ganglion (SCG) was described a long time ago. BK increases the excitability (membrane depolarization at rest and reduction of the spike frequency adaptation (SFA)) of rat SCG (rSCG) neurons [4,12,13,14]. Studies have suggested that depolarization of presynaptic sympathetic-neuron terminals by BK induces the release of prostanoids which acting on nociceptor terminals may induce hyperalgesia. Sympathectomy strongly reduces chloroform-induced hyperalgesia and its exacerbation by BK [4,17]

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