Activity-dependent modulation of neuronal K(V) channels by retinoic acid enhances Ca(V) channel activity

The metabolite of vitamin A, retinoic acid (RA), is known to affect synaptic plasticity in the nervous system and to play an important role in learning and memory. A ubiquitous mechanism by which neuronal plasticity develops in the nervous system is through modulation of voltage-gated Ca(2+) (Ca(V)) and voltage-gated K(+) channels. However, how retinoids might regulate the activity of these channels has not been determined. Here, we show that RA modulates neuronal firing by inducing spike broadening and complex spiking in a dose-dependent manner in peptidergic and dopaminergic cell types. Using patch-clamp electrophysiology, we show that RA-induced complex spiking is activity dependent and involves enhanced inactivation of delayed rectifier voltage-gated K(+) channels. The prolonged depolarizations observed during RA-modulated spiking lead to an increase in Ca(2+) influx through Ca(V) channels, though we also show an opposing effect of RA on the same neurons to inhibit Ca(2+) influx. At physiological levels of Ca(2+), this inhibition is specific to Ca(V)2 (not Ca(V)1) channels. Examining the interaction between the spike-modulating effects of RA and its inhibition of Ca(V) channels, we found that inhibition of Ca(V)2 channels limits the Ca(2+) influx resulting from spike modulation. Our data thus provide novel evidence to suggest that retinoid signaling affects both delayed rectifier K(+) channels and Ca(V) channels to fine-tune Ca(2+) influx through Ca(V)2 channels. As these channels play important roles in synaptic function, we propose that these modulatory effects of retinoids likely contribute to synaptic plasticity in the nervous system.