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

Ji Ye Wei, Ethan D. Cohen, Hans G. Genieser, Colin J. Barnstable

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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. Using Xenopus 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.

Original languageEnglish (US)
Pages (from-to)53-64
Number of pages12
JournalJournal of Molecular Neuroscience
Issue number1
StatePublished - 1998

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience


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