Soluble guanylyl cyclase (sGC) is a highly sensitive nitric oxide (NO) receptor, which plays a key role in neurotransmission, platelet and vascular function. Because diminished sGC function promotes coronary artery disease, atherosclerosis, hypertension, heart attacks and vascular disorders, maintaining proper function of sGC is an important public health issue. Understanding the mechanisms of sGC function and regulation is essential for improving existing and developing new sGC-based therapies. While NO-dependent activation of sGC has been extensively investigated, the process of sGC deactivation is poorly understood. Fast deactivation is essential to properly time sGC cell signaling, but may be disadvantageous for sustaining activated sGC for therapeutic purposes. Although published reports indicate that some proteins involved in protein maturation and folding affect the activity of intracellular sGC 9-12, these effects are most likely not specific to sGC. We have recently identified G-protein signaling modulator proteins GPSM1 and GPSM2 as a new type of sGC modulators, which associate with sGC and attenuate its activation. Our preliminary studies show a predominant expression of GPSM1 in mouse aorta and demonstrate that mice lacking GPSM1 have increased sGC activity in aorta and a longer response to sGC activators. Our long-term goal is to determine how regulation of sGC can be manipulated for therapeutic purposes. Based on preliminary studies, our central hypothesis is that GPSM1 protein is a critical factor that modulates sGC function in normal and disease vascular smooth muscles (VSMC) and mediates the crosstalk between NO/cGMP and G?i-dependent signaling. The main objectives of the study are to identify the molecular mechanism by which GPSM1 modulate sGC, to characterize the effects of this modulation in animal models, and to determine how sGC-GPSM1 communication affects G?i-dependent signaling in VSMC. We will test this hypothesis by: a) determining the changes in sGC-dependent vascular function in GPSM1-/- mice; b) establishing the fundamental step(s) in negative modulation of sGC by GPSM1, and c) elucidating the effect of GPSM1 on communication between sGC- and G?i-dependent signaling pathways in VSMC. This study is significant because it addresses the regulation of sGC, and enzyme whose function play an important role in health and disease processes. The proposal is innovative because it establishes the basis for the rational design of new pharmacological therapies that directly target the contact between sGC and GPSM1 and augment the efficacy of existing sGC-based therapies.
The proposed research is relevant to public health because investigating the mechanisms that regulate the function of soluble guanylyl cyclase (sGC) will provide new knowledge necessary for the development and implementation of new sGC-directed therapies. Thus, the proposed research is relevant to NIH mission as it provides fundamental knowledge that will help to extend healthy life and reduce the burden of cardiovascular diseases.
