Retinoid receptor-based signaling plays a role in voltage-dependent inhibition of invertebrate voltage-gated Ca2+ channels

Abstract

Edited by Mike Shipston The retinoic acid receptor (RAR) and retinoid X receptor (RXR) mediate the cellular effects of retinoids (derivatives of vitamin A). Both RAR and RXR signaling events are implicated in hippocampal synaptic plasticity. Furthermore, retinoids can interact with calcium signaling during homeostatic plasticity. We recently provided evidence that retinoids attenuate calcium current (I Ca) through neuronal voltage-gated calcium channels (VGCCs). We now examined the possibility that constitutive activity of neuronal RXR and/or RAR alters calcium influx via the VGCCs. We found that in neurons of the mollusk Lymnaea stagnalis, two different RXR antagonists (PA452 and HX531) had independent and opposing effects on I Ca that were also time-dependent; whereas the RXR pan-antagonist PA452 enhanced I Ca , HX531 reduced I Ca. Interestingly, this effect of HX531 occurred through voltage-dependent inhibition of VGCCs, a phenomenon known to influence neurotransmitter release from neurons. This inhibition appeared to be independent of G proteins and was largely restricted to Ca v 2 Ca 2؉ channels. Of note, an RAR pan-antagonist, LE540, also inhibited I Ca but produced G protein-dependent, voltage-dependent inhibition of VGCCs. These findings provide evidence that retinoid receptors interact with G proteins in neurons and suggest mechanisms by which retinoids might affect synaptic calcium signaling. Voltage-gated Ca 2ϩ channels (VGCCs) 2 play a prominent role in the functioning of both vertebrate and invertebrate nervous systems. High voltage-activated VGCCs include both Ca v 1 (L-type) and Ca v 2 (non-L-type) channels. In the nervous system, Ca v 1 channels are generally involved in the regulation of gene transcription, whereas Ca v 2 channels play an important role in neurotransmitter release (1). Importantly, high voltageactivated channels are modulated by diverse signaling pathways and can therefore contribute to dynamic changes in cell function.

Conserved biophysical features of the CaV2 presynaptic Ca2+ channel homologue from the early-diverging animal Trichoplax adhaerens

“…Previously, the Ca V 2 channel cloned from the snail L. stagnalis was reported to lack voltage-dependent G-protein inhibition ( 91 ), suggesting that this important neuromodulatory process is unique to vertebrates and closely related animals. However, subsequent work in cultured Lymnaea neurons revealed that endogenous presynaptic Ca V channel currents could be inhibited by activation of dopamine D2 GPCRs ( 92 ) and that G-protein inhibition of calcium currents occurs and can be alleviated by strong depolarizing prepulses ( 92 , 93 ). This suggests that GPCR signaling and specifically Gβγ modulation of presynaptic Ca V 2 channels was present in the common ancestor of animals with bilateral symmetry ( i.e.…”

“…Strong depolarizations can alleviate Gβγ binding, permitting a temporary relief of neuromodulatory inhibition of presynaptic Ca V 2 channels, observed for example during bouts of heightened electrical activity, such as action potential bursts. This form of regulation appears conserved between vertebrates and invertebrates, present in neurons isolated from the snail central nervous system ( 92 , 93 ). Our inability to observe voltage-dependent Gβγ inhibition of the TCa V 2 channel, co-expressed with cloned Trichoplax G-protein subunits, suggests that placozoans lack the capacity for this type of regulation.…”

“…For the snail channel, replacing these regions with corresponding sequences from rat Ca V 2.2 failed to produce voltage-dependent G-protein inhibition, even after co-expression with rat Gβγ ( 91 ), suggesting that additional structural features are required for the interaction. However, whereas the Lymnaea channel lacked this capacity in vitro , endogenous Ca V channel currents recorded in neurons were reported to exhibit voltage-dependent G-protein inhibition ( 92 , 93 ). In preparing for our research, we reasoned that the noted inconsistency was due to sequence divergence between the mammalian G proteins used in the in vitro studies, versus the endogenous G proteins found in Lymnaea neurons.…”

“…Last, although fast Gβγ regulation was not evident in our experiments for TCa V 2, it is possible that slow GPCR regulation might occur in vivo through other GPCR-dependent intracellular signaling pathways. Similar to fast Gβγ inhibition, slow GPCR regulation of Ca V 2 channels is conserved in the nervous systems of vertebrates and invertebrates ( 91 , 92 , 93 , 144 ).…”

Serum Levels of Vitamin A and Vitamin D and Their Association With Symptoms in Children With Attention Deficit Hyperactivity Disorder

“…Imaging studies on brain structures have revealed that children and adolescents suffering from ADHD have decreased intracranial and hippocampal volume (45). Retinoic acid binds to the RXR, and is implicated in hippocampal synaptic plasticity (46)(47)(48). In vivo studies have revealed that VA deficiency damages hippocampal synaptic plasticity and impairs spatial learning and working memory mediated by retinoic acid nuclear receptor-α (20,21).…”