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Functional roles of isoforms of NO-sensitive guanylyl cyclase

Most of the effects of the signalling molecule nitric oxide (NO) are mediated by the stimulation of the NO-sensitive guanylyl cyclase (GC) and the subsequent increase in cGMP formation. The enzyme contains a prosthetic heme group which mediates NO stimulation. NO/cGMP signalling plays an important role in the vascular system and has been proposed to participate in synaptic plasticity in brain.

Two isoforms of NO-sensitive GC have been identified to date that share regulatory properties but differ in the subcellular localization; the more ubiquitously expressed α1β1 heterodimer (α1-GC) and the α2β1 isoform (α2-GC) mainly expressed in brain. Knock-out mice in which either one the α subunits is deleted reveal a loss of the respective GC isoform. The α1-GC and α2-GC KO mice do not show up-regulation of the remaining non-deleted isoform and therefore provide information about the functional roles of the isoforms.

In the vascular system, α1-GC was shown to represent the major GC isoform with α2-GC amounting only to about 6% of WT enzyme in aorta. Surprisingly, α2-GC was able to mediate full relaxation in response to NO showing that small cGMP increase are sufficient to induce the physiological response and that α2-GC functionally is able to substitute for α1-GC in α1-deficient rings.

To obtain information about the neuronal function of the isoforms, long term potentiation (LTP) was measured in the visual cortex. NO-dependent LTP was absent in either one of isoform deficient KO mice but was reconstituted with a cGMP analogue in both strains. The results suggest that the GC isoforms play distinct roles in LTP and cannot substitute for each other. Further experiments have to show whether both GC isoforms are also required for LTP in other brain regions i.e. for hippocampal LTP and whether the KO mice show any behavioural alterations.

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Correspondence to Doris Koesling.

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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 (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Koesling, D., Mergia, E., Taqatqeh, F. et al. Functional roles of isoforms of NO-sensitive guanylyl cyclase. BMC Pharmacol 7 (Suppl 1), S44 (2007).

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