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Substituted cGMP analogs can act as selective agonists of the rod photoreceptor cGMP-gated cation channel

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Abstract

Cyclic nucleotide-gated (CNG) channels are expressed in many cell types in both the nervous system and nonexcitable tissues. In order to understand the roles of cGMP-gated channels, and to distinguish actions of cGMP mediated through CNG channels from those through cGMP-dependent protein kinase (G-kinase), several new cGMP analogs were tested for potency as CNG channel agonists. UsingXenopus oocytes expressing the rat rod cGMP-gated ion channel α-subunit, we showed that an analog containing a pCPT group at the 8-position, 8-pCPT-cGMP, was 80 times more potent than cGMP and 14 times more potent than 8-Br-cGMP. 8-pCPT-cGMP is the most potent CNG channel agonist so far described and also has the advantages of much better membrane permeability as well as much higher resistance to PDE-hydrolysis, as compared with 8-Br-cGMP. Modification of both 8-Br-cGMP and 8-pCPT-cGMP by introduction of a sulphur atom into the cyclic phosphate group gave smaller changes in agonist efficiency. Both Sp-8-Br-cGMPS and Sp-8-pCPT-cGMPS acted as agonists of CNG channels and are also G-kinase activators. In contrast, Rp-8-Br-cGMPS was a channel agonist, with an EC50 of 173.5 µM, but a G-kinase antagonist with a Ki of 4 µM. Finally, Rp-8-pCPT-cGMPS was a channel agonist and showed additional noncompetitive antagonist activity at higher concentrations. The results suggest that 8-pCPT-cGMPS is a highly potent photoreceptor CNG channel agonist with high membrane permeability and PDE-resistance and furthermore Rp-8-Br-cGMPS can be used to test whether the actions of cGMP are selectively mediated by CNG channels.

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Authors and Affiliations

  1. Department of Ophthalmology and Visual Science, Yale University School of Medicine, PO Box 208061, 06520-8061, New Haven, CT

    Ji-Ye Wei, Ethan D. Cohen & Colin J. Barnstable

  2. BIOLOG Life Science Institute, Research Laboratory and Biochemicals, PO Box 107125, D-28071, Bremen, Germany

    Hans-G. Genieser

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  1. Ji-Ye Wei
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Wei, JY., Cohen, E.D., Genieser, HG. et al. Substituted cGMP analogs can act as selective agonists of the rod photoreceptor cGMP-gated cation channel. J Mol Neurosci 10, 53–64 (1998). https://doi.org/10.1007/BF02737085

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