PT  - JOURNAL ARTICLE
AU  - Demian Park
AU  - Kathleen Dunlap
TI  - Dynamic Regulation of Calcium Influx by G-Proteins, Action Potential Waveform, and Neuronal Firing Frequency
AID  - 10.1523/JNEUROSCI.18-17-06757.1998
DP  - 1998 Sep 01
TA  - The Journal of Neuroscience
PG  - 6757--6766
VI  - 18
IP  - 17
4099  - http://www.jneurosci.org/content/18/17/6757.short
4100  - http://www.jneurosci.org/content/18/17/6757.full
SO  - J. Neurosci.1998 Sep 01; 18
AB  - 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 membrane potential and G-proteins on Ca2+ influx in a physiological context, we have measured N-type Ca2+ currents evoked by action potential waveforms in voltage-clamped chick dorsal root ganglion neurons. We have quantified the effect of varying action potential waveforms and frequency on the shape of Ca2+ current in the presence and absence of transmitters (GABA or norepinephrine) that inhibit N current. Our results demonstrate that both the profile of Ca2+ entry and the time course and magnitude of its transmitter-induced inhibition are sensitive functions of action potential waveform and frequency. Increases in action potential 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 short-duration action potentials and decreases exponentially with increasing duration. Increases in action potential frequency promote a voltage-dependent inactivation of Ca2+ influx. In channels exposed to GABA or 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 changing physiological environment. Such variations are likely to be significant for the control of Ca2+-dependent cellular responses in all tissues.