Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system.
In the vascular system, the receptor for the signaling molecule NO, guanylyl cyclase (GC), mediates smooth muscle relaxation and inhibition of platelet aggregation by increasing intracellular cyclic GMP (cGMP) concentration. The heterodimeric GC exists in 2 isoforms (alpha1-GC, alpha2-GC) with indistinguishable regulatory properties. Here, we used mice deficient in either alpha1- or alpha2-GC to dissect their biological functions. In platelets, alpha1-GC, the only isoform present, was responsible for NO-induced inhibition of aggregation. In aortic tissue, alpha1-GC, as the major isoform (94%), mediated vasodilation. Unexpectedly, alpha2-GC, representing only 6% of the total GC content in WT, also completely relaxed alpha1-deficient vessels albeit higher NO concentrations were needed. The functional impact of the low cGMP levels produced by alpha2-GC in vivo was underlined by pronounced blood pressure increases upon NO synthase inhibition. As a fractional amount of GC was sufficient to mediate vasorelaxation at higher NO concentrations, we conclude that the majority of NO-sensitive GC is not required for cGMP-forming activity but as NO receptor reserve to increase sensitivity toward the labile messenger NO in vivo.
Mergia
Evanthia
E
Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany.
Friebe
Andreas
A
Dangel
Oliver
O
Russwurm
Michael
M
Koesling
Doris
D
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D018390:Gene Targeting; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014664:Vasodilation
D007527:Isoenzymes; D021122:Protein Subunits; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP