Flufenamic acid modulates multiple currents in gonadotropin-releasing hormone neurons.
Reproduction in mammals is dependent upon the appropriate neurosecretion of gonadotropin-releasing hormone (GnRH), yet the endogenous generation of activity underlying GnRH secretion remains poorly understood. We have demonstrated that the depolarizing afterpotential (DAP), which modulates bursting activity, is reduced in isolated GnRH neurons from aged animals. Calcium-activated non-specific cation (CAN) channels contribute to the DAP in other vertebrate neurosecretory cells. We used the CAN channel blocker flufenamic acid (FFA) to examine the contribution of CAN channels to the DAP in GnRH neurons during aging. Recordings were performed on isolated fluorescent GnRH neurons from young, middle-aged and aged female mice. Flufenamic acid inhibited spontaneous activity, but significantly increased the DAP in neurons from young and middle-aged animals. Apamin did not significantly potentiate the DAP, but did reduce the effects of FFA, suggesting that the increased DAP is partially due to blockade of apamin-sensitive SK channels. Flufenamic acid increased the current underlying the DAP (I(ADP)) and decreased the preceding fast outward current (I(OUT)) at all ages. These current responses were not affected by apamin, but TEA evoked similar changes. Thus, a potassium current, likely mediated through BK channels, contributes to the fast AHP and appears to offset the DAP; this current is sensitive to FFA, but insensitive to age. The effect of FFA on the DAP, but not I(ADP), is diminished in aged animals, possibly reflecting an age-related modulation of the apamin-sensitive SK channel. Future studies will examine the expression of SK channels during the aging process in GnRH neurons.
Wang
Yong
Y
Department of Biological Engineering, University of Missouri, Dalton Cardiovascular Research Center, Columbia, MO 65211, USA.
Kuehl-Kovarik
M Cathleen
MC
D000200:Action Potentials / Q000187:drug effects*; D000367:Age Factors; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D005260:Female; D005439:Flufenamic Acid / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010052:Ovariectomy / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D013779:Tetrodotoxin; D005439:Flufenamic Acid; D019789:Tetraethylammonium