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 Ca²⁺ (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 Ca²⁺ influx through Ca_V channels, though we also show an opposing effect of RA on the same neurons to inhibit Ca²⁺ influx. At physiological levels of Ca²⁺, this inhibition is specific to Ca_V2 (not Ca_V1) channels. Examining the interaction between the spike-modulating effects of RA and its inhibition of Ca_V channels, we found that inhibition of Ca_V2 channels limits the Ca²⁺ 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 Ca²⁺ influx through Ca_V2 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.