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Open AccessArticle

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

Laboratory of Neuroscience, Biomedical Research Centre (CINBIO), University of Vigo, 36310 Vigo, Spain
*
Author to whom correspondence should be addressed.
Present Address: Department of Functional Architecture of Memory, Leibniz Institute for Neurobiology, Brenneckestraße 6, 39118 Magdeburg, Germany.
Int. J. Mol. Sci. 2020, 21(2), 389; https://doi.org/10.3390/ijms21020389
Received: 29 November 2019 / Revised: 30 December 2019 / Accepted: 2 January 2020 / Published: 8 January 2020
(This article belongs to the Section Molecular Pharmacology)
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. View Full-Text
Keywords: bradykinin; perforated patch; PIP2; riluzole; sympathetic neurons; TREK currents bradykinin; perforated patch; PIP2; riluzole; sympathetic neurons; TREK currents
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MDPI and ACS Style

Rivas-Ramírez, P.; Reboreda, A.; Rueda-Ruzafa, L.; Herrera-Pérez, S.; Lamas, J.A. PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons. Int. J. Mol. Sci. 2020, 21, 389. https://doi.org/10.3390/ijms21020389

AMA Style

Rivas-Ramírez P, Reboreda A, Rueda-Ruzafa L, Herrera-Pérez S, Lamas JA. PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons. International Journal of Molecular Sciences. 2020; 21(2):389. https://doi.org/10.3390/ijms21020389

Chicago/Turabian Style

Rivas-Ramírez, Paula; Reboreda, Antonio; Rueda-Ruzafa, Lola; Herrera-Pérez, Salvador; Lamas, J. A. 2020. "PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons" Int. J. Mol. Sci. 21, no. 2: 389. https://doi.org/10.3390/ijms21020389

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