Date of Graduation
Masters of Science (MS)
Soluble guanylyl cyclase (sGC) plays a key role in the nitric oxide (NO) signaling pathway, where it functions as an NO receptor and generator of a secondary intracellular messenger, cGMP. In addition to NO, investigators have identified a number of proteins that interact with sGC and modulate its function. For example, the interaction of sGC with ADP-ribosylation factor GTPase activating protein 1 (AGAP1) governs sGC’s intracellular distribution and therefore mediates localized production of cGMP. Interactions of sGC with heat-shock protein 90 (HSP90) or HSP70 promote the extent of sGC activation upon NO stimulation, while interaction of sGC with the η subunit of chaperonin-containing T-complex polypeptide 1 (CCTη) or with protein disulfide isomerase (PDI) decreases NO-stimulated cGMP production. Previous experiments demonstrated that the G-protein signaling modulator protein, activator of G-protein signaling 3 (AGS3), attenuates the response of sGC to activators in cell lysates.
In this report, we provide evidence that sGC activity and responsiveness are increased in AGS3-deficient mice. We found that AGS3-deficient mice not only have a lower resting blood pressure than their wild-type counterparts, but also are more sensitive to sGC agonists (DEA-NO and BAY41-2272). Hematoxylin and eosin staining of aorta sections did not show any significant no morphological differences between AGS3-/- and wild type mice. However, sGC in aortic lysates from AGS3-/- mice generated a higher level of cGMP in response to the NO-donor, DEA-NO, than in wild type lysates. These data indicate that, in the absence of AGS3, sGC activity is increased within smooth muscle cells of aortic tissue. In summary, the data from the present study suggests that AGS3 is a negative regulator of sGC vascular function.
cGMP, sGC, vessel dilation, NO-signaling, Nitric Oxide, AGS3, Activator of G-protein Signaling