DYNAMIC REGULATION OF CALCIUM INFLUX BY G-PROTEINS, ACTION-POTENTIAL WAVE-FORM, AND NEURONAL FIRING FREQUENCY

The time course of Ca2+ channel activation and the amplitude and rate of change of Ca2+ influx are primarily controlled by membrane voltage. G-protein-coupled signaling pathways, however, modulate the efficacy of membrane voltage on channel gating. To study the interactions of me mbrane potential and G-proteins on Ca2+ influx in a physiological cont ext, we have measured N-type Ca2+ currents evoked by action potential waveforms in voltage-clamped chick dorsal root ganglion neurons. We ha ve quantified the effect of varying action potential waveforms and fre quency on the shape of Ca2+ current in the presence and absence of tra nsmitters (GABA or norepinephrine) that inhibit N current. Our results demonstrate that both the profile of Ca2+ entry and the time course a nd magnitude of its transmitter-induced inhibition are sensitive funct ions of action potential waveform and frequency. Increases in action p otential duration enhance total Ca2+ entry, but they also prolong and blunt Ca2+ signals by slowing influx rate and reducing peak amplitude. Transmitter-mediated inhibition of Ca2+ entry is most robust with sho rt-duration action potentials and decreases exponentially with increas ing duration. Increases in action potential frequency promote a voltag e-dependent inactivation of Ca2+ influx. In channels exposed to GABA o r norepinephrine, however, this inactivation is counteracted by a time - and frequency-dependent relief of modulation. Thus, multiple stimuli are integrated by Ca2+ channels, tuning the profile of influx in a ch anging physiological environment. Such variations are likely to be sig nificant for the control of Ca2+-dependent cellular responses in all t issues.