Modulation of Voltage-Gated Ca2+ Channels by Retinoic Acid Signaling

Abstract

Retinoic acid (RA), the active metabolite of vitamin A, has an established role in development of the nervous system, but has recently emerged as a critical regulator of adult nervous system function. RA is important for learning and memory in both vertebrates and invertebrates. It is also important for synaptic plasticity at rodent hippocampal synapses and is known to interact with Ca2+ signaling to regulate receptor expression and influence synaptic transmission. How RA signaling might mediate plasticity in an invertebrate nervous system has not yet been studied. Voltage-gated Ca2+ channels (CaV) represent a ubiquitous means of Ca2+ entry into a cell, and which regulate neuronal functioning (such as gene expression and neurotransmitter release). As such, CaV channels represent a potentially important locus for inducing plasticity in both vertebrates and invertebrates. It is not known in any species, whether RA might mediate changes in neuronal communication by influencing the functional properties of CaV channels. Here I show, utilizing cultured neurons from the molluscan pond snail, Lymnaea stagnalis, that RA signaling modulates CaV channel function. RA signaling inhibited CaV channel function by shifting the voltage dependence of channel activation to more depolarized potentials. I found that RA also produced spike broadening and activity-dependent complex spiking, an effect I determined was mediated by RA-induced inhibition of delayed rectifier voltage-gated K+ channels (KV), (and enhanced inactivation of these KV channels). Paradoxically, the effect of RA to induce spike broadening and activity-dependent complex spiking, enhanced Ca2+ influx through CaV channels. However, the concurrent inhibition of CaV2 channels limited this enhanced Ca2+ influx. I also provide evidence that constitutive/basal retinoid receptor signaling upregulates CaV channel function. I show that a retinoic acid receptor (RAR) antagonist produced G-protein-mediated voltage-dependent inhibition of CaV channels, a ubiquitous form of presynaptic plasticity that occurs at vertebrate synapses. I also show that a retinoid X receptor (RXR) antagonist produced a novel G-protein-independent form of voltage-dependent inhibition of CaV channels. Overall, my study indicates that retinoid signaling diversely regulates CaV channel function in this invertebrate species and provides insights into the mechanisms by which RA signaling might mediate neuronal and/or synaptic plasticity.