Direct gating by retinoic acid of retinal electrical synapses
AUTOR(ES)
Zhang, Dao-Qi
FONTE
The National Academy of Sciences
RESUMO
Retinoic acid (RA), a signaling molecule derived from vitamin A, controls growth and differentiation of a variety of cell types through regulation of gene transcription. In the vertebrate retina, RA also regulates gap junction-mediated physiological coupling of retinal neurons through a nontranscriptional mechanism. Here we report that RA rapidly and specifically modulates synaptic transmission at electrical synapses of cultured retinal horizontal cells through an external RARβ/γ-like binding site, the action of which is independent of second messenger cascades. External application of all-trans retinoic acid (at-RA) reversibly reduced the amplitude of gap junctional conductance in a dose-dependent manner, but failed to affect non-gap-junctional channels, including glutamate receptors. In contrast, internal dialysis with at-RA was ineffective, indicating an external site of action. Selective RARβ/γ ligands, but not an RARα-selective agonist, mimicked the action of at-RA, suggesting that gating of gap junctional channels is mediated through an RARβ/γ-like binding site. At-RA did not act on gap junctional conductance by lowering [pH]i or by increasing [Ca2+]i. A G protein inhibitor and protein kinase inhibitors did not block at-RA uncoupling effects indicating no second messenger systems were involved. Direct action of at-RA on gap junction channels was further supported by its equivalent action on whole-cell hemi-gap-junctional currents and on cell-free excised patch hemichannel currents. At-RA significantly reduced single-channel open probability but did not change unitary conductance. Overall, the results indicate that RA modulates horizontal cell electrical synapses by activation of novel nonnuclear RARβ/γ-like sites either directly on, or intimately associated with, gap junction channels.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18991Documentos Relacionados
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