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Flufenamic Acid Affects Multiple Currents and Causes Intracellular Ca²⁺ Release in Aplysia Bag Cell Neurons

Department of Physiology and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada

Submitted 12 February 2008; accepted in final form 17 April 2008

Flufenamic acid (FFA) is a nonsteroidal antiinflammatory agent, commonly used to block nonselective cation channels. We previously reported that FFA potentiated, rather than inhibited, a cation current in Aplysia bag cell neurons. Prompted by this paradoxical result, the present study examined the effects of FFA on membrane currents and intracellular Ca²⁺ in cultured bag cell neurons. Under whole cell voltage clamp, FFA evoked either outward (I_out) or inward (I_in) currents. I_out had a rapid onset, was inhibited by the K⁺ channel blocker, tetraethylammonium, and was associated with both an increase in membrane conductance and a negative shift in the whole cell current reversal potential. I_in developed more slowly, was inhibited by the cation channel blocker, Gd³⁺, and was concomitant with both an increased conductance and positive shift in reversal potential. FFA also enhanced the use-dependent inactivation and caused a positive-shift in the activation curve of the voltage-dependent Ca²⁺ current. Furthermore, as measured by ratiometric imaging, FFA produced a rise in intracellular Ca²⁺ that persisted in the absence of extracellular Ca²⁺ and was reduced by depleting either the endoplasmic reticulum and/or mitochondrial stores. Ca²⁺ appeared to be involved in the activation of I_in, as strong intracellular Ca²⁺ buffering effectively eliminated I_in but did not alter I_out. Finally, the effects of FFA were likely not due to block of cyclooxygenase given that the general cyclooxygenase inhibitor, indomethacin, failed to evoke either current. That FFA influences a number of neuronal properties needs to be taken into consideration when employing it as a cation channel antagonist.