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Next Article 
Journal of Neuroscience, Vol 16, 1285-1293, Copyright © 1996 by Society for Neuroscience
Antagonists of cyclic nucleotide-gated channels and molecular mapping of their site of action
RH Kramer and GR Tibbs
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Florida 33101, USA.
Activation of photoreceptor and olfactory cyclic nucleotide-gated (CNG)
channels involves distinct ligand-binding and channel-gating reactions. To
dissociate binding from gating, we identified the first competitive
antagonists of CNG channels: specific phosphorothioate derivatives of cAMP
and cGMP. We also identified membrane-permeant forms of these molecules
that are antagonists and that will be useful for elucidating physiological
roles for CNG channels in intact cells. The photoreceptor and olfactory CNG
channels determine which of the phosphorothioate derivatives are agonists
and which are antagonists based on different structural features of the
ligand. The photoreceptor channel uses the nature of the purine ring
(adenine vs guanine), whereas the olfactory channel uses the isomeric
position of the thiophosphate S atom (Rp vs Sp). Interestingly, the same
ligand, Rp-cGMPS, has opposite effects on the two channels, activating the
photoreceptor channel and antagonizing the olfactory channel. Because
Rp-cGMPS binds to both channels but activates only one, the channels must
differ in a protein region that couples binding to gating. Chimeric
photoreceptor and olfactory CNG channels reveal that the cytoplasmic
C-terminal domain determines whether bound ligand activates the channel
successfully. Hence, the C terminus contains not only the cyclic
nucleotide-binding site, but also a region that couples ligand binding to
channel gating.
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