Roles of arachidonic acid, lipoxygenases and phosphatases in calcium‐dependent modulation of M‐current in bullfrog sympathetic neurons.

Abstract

1. M-current (IM) is regulated by intracellular free Ca2P ([Ca2+]1). Suppression and overrecovery of IM induced by muscarine and luteinizing-hormone releasing hormone (LHRH) are also regulated by [Ca2+]1. The role of the arachidonic acid (AA) pathway in the Ca2+-dependent modulation of IM was investigated using whole-cell voltage clamp and intracellular perfusion in dissociated bullfrog sympathetic B neurons. 3. AA (6-120 ,uM) increased IM by about 50% of the control current in a Ca2+-dependent manner.4. Enhancements of IM by Ca2' and AA were blocked by the lipoxygenase (LO) inhibitors nordihydroguaiaretic acid (NDGA; 1-5 /uM) and 5,8,11-eicosatrynoic acid (ETI; 10 /UM). The cyclo-oxygenase inhibitor indomethacin (10 /uM) had no effect.

M1Muscarinic Receptors Inhibit L-type Ca2+Current and M-Current by Divergent Signal Transduction Cascades

“…Moreover, our unanticipated findings that OPC, BSA, or the absence of cPLA 2 greatly attenuated M-current recovery from inhibition indicated a role for cPLA 2 and AA in recovery from the inhibitory process. A role for AA in regulating M-current is supported by the finding that exogenously applied AA enhances M-current in frog sympathetic neurons (Villarroel, 1994;Yu, 1995).…”

“…AA may mediate M 1 R signaling by activating additional downstream molecules such as kinases (Gailly et al, 1997;Liao et al, 2004) or phosphatases, as has been proposed for AA-mediated inhibition of T-and cardiac L-currents (PetitJacques and Hartzell, 1996;Zhang et al, 2000) and AA-mediated M-current enhancement (Yu, 1995). This model does not require a loss of PIP 2 bound to channels.…”

“…These differences indicate that AA uses additional, novel mechanisms to regulate M-current compared with Ca 2ϩ channels and other K v channel activity (Oliver et al, 2004). Moreover, this signaling cascade appears remarkably similar to the PLA 2 -sensitive pathway responsible for M-current over-recovery observed after washing out of agonist in other cell types (Robbins et al, 1993;Villarroel, 1994;Yu, 1995). Mechanistically, these unexpected findings suggest that, to observe the effects of AA on recovery, sufficient PIP 2 must be present in the membrane and/or associated with the channels.…”

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

“…Arachidonic acid (Schweitzer et al 1990;Behe et al 1992;Villarroel 1994;Yu 1995) and other PUFAs (Behe et al 1992) increase the M-current. PUFA effects on the M-current are however complex.…”

Novel Effects of 5,8,11‐Eicosatriynoic Acid, a Lipoxygenase Inhibitor, on Ca2+ Mobilization in Madin Darby Canine Kidney Cells

“…5,8,11-Eicosatriynoic acid has been demonstrated to be a potent inhibitor of 5-and 12-lipoxygenases in preparations from different origins. In intact cell preparations, 5,8,11-eicosatriynoic acid prevented the biosynthesis of leukotriene C4 (ID 50 Ω5 mM) by mastocytoma cells (Orning & Hammarstrom 1980), inhibits lipoxygenase-mediated aggregation of neutrophils (Patarroyo & Jondal 1985;Bunce et al 1994), and inhibited M-current in bullfrog sympathetic neurons (Yu 1995). In broken cell preparations, 5,8,11-eicosatriynoic acid inhibited soybean lipoxygenases with a K m of 1.3 mM (Kuhn et al 1984).…”