Voltage-Dependent Kappa Opioid Modulation of Calcium Currents Elicited by Action Potential Waveforms in Neurohypophysial Terminals

Abstract

Release of neurotransmitter is activated by the influx of calcium. Inhibition of Ca2+ channels results in less calcium influx into the terminal and, presumably, a reduction in transmitter release. In the nerve terminals of the neurohypophysis, voltage-gated calcium channels (VGCC) are primarily controlled by membrane voltage and their activity can be modulated, in a voltage-dependent manner, by their interaction with G-protein subunits. Endogenous opioids also affect (inhibit) these calcium channels, upon binding to μ- and κ-receptors at the terminals.Voltage-dependent relief of G-protein inhibition of VGCC is achieved with either a depolarizing square pre-pulse or by action potential waveforms. Both protocols were tested in the presence and absence of opioid agonists targeting the μ- and κ-receptors. The κ-opioid VGCC inhibition is relieved by such pre-pulses, suggesting that this receptor is involved in a voltage-dependent membrane-delimited G-protein pathway. In contrast, μ-opioid inhibition of VGCC is not relieved by such pre-pulses, indicating a voltage-independent diffusible second-messenger signaling pathway. Furthermore, κ-opioid inhibition is also relieved during stimulation with action potential bursts with physiological characteristics. This indicates the possibility of activity-dependent modulation in vivo.Differences in the facilitation of Ca2+ channels due to specific G-protein modulation during a burst of action potentials may contribute to the fine-tuning of Ca2+-dependent neuropeptide release in other central nervous system synapses, as well. [Supported by NIH Grant NS29470].