Retinoic acid inhibits neuronal voltage-gated calcium channels

Retinoic acid is the active metabolite of vitamin A and regulates several important cellular processes by activating retinoic acid receptors (RAR) and retinoid X receptors (RXR). These receptors generally act as transcription factors, though non-genomic actions of both retinoic acid and the receptors have also been reported. One such nongenomic effect includes the modulation of Ca2+ levels during homeostatic synaptic plasticity in the hippocampus. Retinoic acid can thus affect Ca2+ signaling and can potentially control both synaptic plasticity and neuronal firing. However, whether retinoic acid can regulate voltage-gated Ca2+ channels (either via genomic or nongenomic actions), which are fundamental to these processes, has not yet been studied in detail. Here we demonstrate the effects of retinoic acid on the biophysical properties of voltage-gated Ca2+ channels in cultured invertebrate motorneurons. Overnight exposure to physiological concentrations of retinoic acid significantly inhibited the voltage-gated Ca2+ current (I-Ca) in an isomer-dependent manner. Specifically, all-trans retinoic acid (atRA), but not 9-cis RA (9cRA), depolarized the voltage of half-maximal activation of I-Ca. AtRA also reduced the rate of channel activation and delayed recovery from inactivation. We provide evidence that both L-type and non-L-type voltage-gated Ca2+ channels are affected by atRA, as both nifedipine-sensitive and nifedipine-resistant I-Ca were inhibited in these neurons. These effects of retinoic acid are thought to be at least partially mediated by the retinoid receptors, as treatment of the neurons with synthetic RAR and RXR agonists produced a similar inhibition of I-Ca