Amplitude-dependent spike-broadening and enhanced Ca2+ signaling in GnRH-secreting neurons

In GnRH-secreting (GT1) neurons, activation of Ca2+-mobilizing receptors in duces a sustained membrane depolarization that shifts the profile of the ac tion potential (AP) waveform from sharp, high-amplitude to broad, low-ampli tude spikes. Here we characterize this shift in the firing pattern and its impact on Ca2+ influx experimentally by using prerecorded sharp and broad A Ps as the voltage-clamp command pulse. As a quantitative test of the experi mental data, a mathematical model based on the membrane and ionic current p roperties of GT1 neurons was also used. Both experimental and modeling resu lts indicated that inactivation of the tetrodotoxin-sensitive Na+ channels by sustained depolarization accounted for a reduction in the amplitude of t he spike upstroke. The ensuing decrease in tetraethylammonium-sensitive Kcurrent activation slowed membrane repolarization, leading to AP broadening . This change in firing pattern increased the total L-type Ca2+ current and facilitated AP-driven Ca2+ entry. The leftward shift in the current-voltag e relation of the L-type Ca2+ channels expressed in GT1 cells allowed the d epolarization-induced AP broadening to facilitate Ca2+ entry despite a decr ease in spike amplitude. Thus the gating properties of the L-type Ca2+ chan nels expressed in GT1 neurons are suitable for promoting AP-driven Ca2+ inf lux in receptor- and non-receptor-depolarized cells.