Calcium and voltage dependent inactivation of sodium and calcium currents limits calcium influx in helisoma neurons

AbstractThe control of free intracellular calcium concentration ([Ca2+]i) is necessary for cell survival because of the ubiquitous and essential role this second messenger plays in regulating numerous intracellular processes. Calcium regulation in neurons is especially vigorous because of the large calcium influx that occurs through voltage‐gated channels during membrane depolarization. In this study we examined changes in ionic currents that can limit calcium influx into neurons during electrical activity. We found that the [Ca2+]i in electrically stimulated Helisoma B4 neurons initially increased to a peak and then relaxed to lower concentrations in tandem with a decline in the action potential peak voltage. The decline in [Ca2+]i and the peak action potential voltage in this sodium and calcium driven neuron was found to be a dual manifestation of INa and ICa inactivation. INa and ICa both displayed voltage dependent inactivation. Additionally, INa and ICa progressively inactivated at [Ca2+]i above 200 nM, concentrations readily attained in electrically stimulated B4 neurons. Calcium and voltage dependent INa and ICa inactivation were found to reduce calcium influx during continuous electrical stimulation by decreasing both the magnitude of ICa that could be activated and the percent of the available ICa that would be activated due to the diminished peak action potential voltage. Calculations based on data herein suggest that the voltage and calcium dependent INa and ICa inactivation that occurs during continuous electrical stimulation dramatically reduces calcium influx in this sodium and calcium driven neuron and thus limits the increase in [Ca2+]i. © 2003 Wiley Periodicals, Inc. J Neurobiol 54: 439–456, 2003