Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in... 1 Previous studies have shown that flupirtine, a centrally acting, non‐opioid analgesic agent, also exhibits neuroprotective activity in focal cerebral ischaemia in mice and reduces apoptosis induced by NMDA, gp 120 of HIV, prior protein fragment or lead acetate as well as necrosis induced by glutamate or NMDA in cell culture. To study the potential mechanism of the neuroprotective action of flupirtine, we investigated whether flupirtine is able to modulate potassium or NMDA‐induced currents in rat cultured hippocampal neurones by use of the whole‐cell configuration of the patch‐clamp technique. 2 We demonstrated that 1 μM flupirtine activated an inwardly rectifying potassium current (Kir) in hippocampal neurones (ΔI=−39±18 pA at −130 mV; n=10). This effect was dose‐dependent (EC50=0.6 μM). The reversal potential for Kir was in agreement with the potassium equilibrium potential predicted from the Nernst equation showing that Kir was predominantly carried by K+. Furthermore, the induced current was blocked completely by Ba2+ (1 mM), an effect typical for Kir. 3 The activation of Kir by flupirtine was largely prevented by pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX‐sensitive G‐protein in the transduction mechanism (ΔI=−3±6 pA at −130 mV; n=8). Inclusion of cyclic AMP in the intracellular solution completely abolished the activation of Kir (n=7). 4 The selective α2‐adrenoceptor antagonist SKF‐86466 (10 μM), the selective 5‐HT1A antagonist NAN 190 as well as the selective GABAB antagonist 2‐hydroxysaclofen (10 μM) failed to block the flupirtine effect on the inward rectifier. 5 Flupirtine (1 μM) could not change the current induced by 50 μM NMDA. 6 These results show that in cultured hippocampal neurones flupirtine activates an inwardly rectifying potassium current and that a PTX‐sensitive G‐protein is involved in the transduction mechanism. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Influence of flupirtine on a G‐protein coupled inwardly rectifying potassium current in hippocampal neurones

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Abstract

1 Previous studies have shown that flupirtine, a centrally acting, non‐opioid analgesic agent, also exhibits neuroprotective activity in focal cerebral ischaemia in mice and reduces apoptosis induced by NMDA, gp 120 of HIV, prior protein fragment or lead acetate as well as necrosis induced by glutamate or NMDA in cell culture. To study the potential mechanism of the neuroprotective action of flupirtine, we investigated whether flupirtine is able to modulate potassium or NMDA‐induced currents in rat cultured hippocampal neurones by use of the whole‐cell configuration of the patch‐clamp technique. 2 We demonstrated that 1 μM flupirtine activated an inwardly rectifying potassium current (Kir) in hippocampal neurones (ΔI=−39±18 pA at −130 mV; n=10). This effect was dose‐dependent (EC50=0.6 μM). The reversal potential for Kir was in agreement with the potassium equilibrium potential predicted from the Nernst equation showing that Kir was predominantly carried by K+. Furthermore, the induced current was blocked completely by Ba2+ (1 mM), an effect typical for Kir. 3 The activation of Kir by flupirtine was largely prevented by pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX‐sensitive G‐protein in the transduction mechanism (ΔI=−3±6 pA at −130 mV; n=8). Inclusion of cyclic AMP in the intracellular solution completely abolished the activation of Kir (n=7). 4 The selective α2‐adrenoceptor antagonist SKF‐86466 (10 μM), the selective 5‐HT1A antagonist NAN 190 as well as the selective GABAB antagonist 2‐hydroxysaclofen (10 μM) failed to block the flupirtine effect on the inward rectifier. 5 Flupirtine (1 μM) could not change the current induced by 50 μM NMDA. 6 These results show that in cultured hippocampal neurones flupirtine activates an inwardly rectifying potassium current and that a PTX‐sensitive G‐protein is involved in the transduction mechanism.

Journal

British Journal of PharmacologyWiley

Published: Dec 1, 1997

References

  • Drug receptors and the inhibition of nerve cells
    North, North
  • Molecular biology of voltage‐dependent potassium channels
    Pongs, Pongs
  • Flupirtine protects neurons against excitotoxic or ischemic damage and inhibits the increase in cytosolic Ca 2+ concentration
    Rupalla, Rupalla; Cao, Cao; Krieglstein, Krieglstein
  • Mode of antinociceptive action of flupirtine in the rat
    Szelenyi, Szelenyi; Nickel, Nickel; Borbe, Borbe; Brune, Brune

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