Direct gating by retinoic acid of retinal electrical synapses

Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14754-9. doi: 10.1073/pnas.010325897.


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 RAR(beta)(/gamma)-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 RAR(beta)(/gamma) ligands, but not an RAR(alpha)-selective agonist, mimicked the action of at-RA, suggesting that gating of gap junctional channels is mediated through an RAR(beta)(/gamma)-like binding site. At-RA did not act on gap junctional conductance by lowering [pH](i) or by increasing [Ca(2+)](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 RAR(beta)(/gamma)-like sites either directly on, or intimately associated with, gap junction channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Bass
  • Cells, Cultured
  • Electrophysiology
  • Gap Junctions / drug effects
  • Gap Junctions / physiology*
  • Glucuronides / metabolism
  • Guanosine Triphosphate / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retina / cytology
  • Retina / physiology*
  • Retinoic Acid Receptor alpha
  • Synapses / physiology*
  • Tretinoin / analogs & derivatives*
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology


  • Glucuronides
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • retinoic acid receptor beta
  • 5,6-epoxyretinoic acid
  • Tretinoin
  • Guanosine Triphosphate
  • Adenosine Triphosphate