Skip to main content

Advertisement

Analysis of cGKI inhibition by Rp-cGMP analogs

Article metrics

  • 874 Accesses

Although it is well established that cGMP has important (patho-)physiological functions, the downstream mediators of cGMP signalling are not well understood. The cGMP-dependent protein kinase type I (cGKI) is an attractive candidate receptor for cGMP. A common approach to distinguish between cGKI-dependent and cGKI-independent cGMP effects is the use of pharmacological "cGKI inhibitors". However, it is increasingly recognized that some of these drugs, such as KT5823, may be less specific than previously thought or may not at all inhibit cGKI activity in intact cells. The Rp-cGMP analogs are reported to inhibit cGKI by binding to the cGMP-binding sites. In this study, we have analysed the effects of two popular Rp-cGMP analogs, Rp-8-Br-PET-cGMPS and Rp-8-pCPT-cGMPS, on basal and cGMP/cGKI-stimulated growth of vascular smooth muscle cells. Surprisingly, neither compound showed a clear inhibition of cell growth and cGKI activity in intact cells as monitored by growth assays and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), respectively. In vitro kinase assays with purified cGKI demonstrated that both Rp-cGMP analogs are partial agonists for cGKI rather than antagonists (see Figure 1). Thus, it appears difficult to interpret data obtained from experiments with Rp-8-Br-PET-cGMPS and Rp-8-pCPT-cGMPS. Both compounds should be used with caution as "cGKI inhibitors".

Figure 1
figure1

Effects of the Rp-cGMP isomers on basal cGKI activity in vitro.

Author information

Correspondence to Nadejda Valtcheva.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Valtcheva, N., Weinmeister, P., Hofmann, F. et al. Analysis of cGKI inhibition by Rp-cGMP analogs. BMC Pharmacol 7, P62 (2007) doi:10.1186/1471-2210-7-S1-P62

Download citation

Keywords

  • Smooth Muscle Cell
  • Vascular Smooth Muscle
  • Vascular Smooth Muscle Cell
  • Intact Cell
  • Partial Agonist