The Journal of General Physiology
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Published online 17 October 2005 doi:10.1085/jgp.200509387
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 126, Number 5, 453-460
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ARTICLE

 Defining the Retinoid Binding Site in the Rod Cyclic Nucleotide-gated Channel

Diana M. Horrigan1, Michelle L. Tetreault1, Natia Tsomaia1, Chrysoula Vasileiou2, Babak Borhan2, Dale F. Mierke1, Rosalie K. Crouch3, and Anita L. Zimmerman1

1 Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown Medical School, Providence, RI 02912
2 Department of Chemistry, Michigan State University, East Lansing, MI 48824
3 Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425

Correspondence to Anita L. Zimmerman: Anita_Zimmerman{at}brown.edu

Rod vision is initiated when 11-cis-retinal, bound within rhodopsin, absorbs a photon and isomerizes to all-trans-retinal (ATR). This triggers an enzyme cascade that lowers cGMP, thereby closing cyclic nucleotide-gated (CNG) channels. ATR then dissociates from rhodopsin, with bright light releasing millimolar levels of ATR. We have recently shown that ATR is a potent closed-state inhibitor of the rod CNG channel, and that it requires access to the cytosolic face of the channel (McCabe, S.L., D.M. Pelosi, M. Tetreault, A. Miri, W. Nguitragool, P. Kovithvathanaphong, R. Mahajan, and A.L. Zimmerman. 2004. J. Gen. Physiol. 123:521–531). However, the details of the interaction between the channel and ATR have not been resolved. Here, we explore the nature of this interaction by taking advantage of specific retinoids and retinoid analogues, namely, ß-ionone, all-trans-C15 aldehyde, all-trans-C17 aldehyde, all-trans-C22 aldehyde, all-trans-retinol, all-trans-retinoic acid, and all-trans-retinylidene-n-butylamine. These retinoids differ in polyene chain length, chemical functionality, and charge. Results obtained from patch clamp and NMR studies have allowed us to better define the characteristics of the site of retinoid–channel interaction. We propose that the cytoplasmic face of the channel contains a retinoid binding site. This binding site likely contains a hydrophobic region that allows the ionone ring and polyene tail to sit in an optimal position to promote interaction of the terminal functional group with residues ~15 Å away from the ionone ring. Based on our functional data with retinoids possessing either a positive or a negative charge, we speculate that these amino acid residues may be polar and/or aromatic.

Abbreviations used in this paper: ATR, all-trans-retinal; ATR-NBu, all-trans-retinylidene-n-butylamine; ATRol, all-trans-retinol; CNG, cyclic nucleotide-gated; DPC, dodecylphosphocholine; NMR, nuclear magnetic resonance.


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