Joint work with Lazar Z. Krsmanovic, Kevin J. Catt, Stanko Stojilkovic.
In many excitable cells, plasma membrane electrical activity and the associated voltage-gated Ca2+ influx are controlled by the filling state of the endoplamic reticulum Ca2+ stores. The mechanism of this process was investigated in differentiated GnRH secreting (GT1) neurons using simultaneous measurements of membrane potential or current and changes in cytosolic Ca2+ concentration [Ca2+]i. GT1 cells exhibited spontaneous action potentials (AP) that were initiated by a slow pacemaker depolarization from a baseline potential between -75 and -50 mV. Cells with more hyperpolarized baseline potentials fired sharp, high amplitude action potentials (neuronal like), whereas more depolarized cells fired lower amplitude, broad action potentials (endocrine like).=20 Tetrodotoxin-sensitive Na+ channels, as well as T-type and L-type Ca2+ channels contributed to action potential firing in neuronal-like action potentials. Due to steady-state inactivation of tetrodotoxin-sensitive Na+ channels and T-type Ca2+ channels, only L-type Ca2+ channels contributed to endocrine-like action potential spiking. Compared to neuronal like action potentials, endocrine action potentials had a greater capacity to drive Ca2+ influx through voltage-gated Ca2+ channels. Depletion of endoplasmic reticulum Ca2+ stores by the activation of Ca2+ mobilizing GnRH receptors or inhibition of the endoplasmic reticulum Ca2+ pump activated a voltage-insensitive, Ca2+ permeable current that depolarized the membrane. This leads to an increase in action potential frequency, as well as the generation of endocrine like action potentials. These results indicate that store depletion increases membrane excitability to facilitate voltage-gated Ca2+ influx in electrically excitable cells.1998-1999 Mathematics in Biology