REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION

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DESCRIPTION (provided by applicant): Our research objective is to determine the signal transduction mechanisms that are unique to, or altered in the human myometrium in preterm labor because this is presently unknown and because current treatments for premature labor (PTL) are wholly inadequate. No matter the varied causes of PTL (fetal or maternal) in any given woman, in unexplained cases, changes will inevitably be found in myometrial signaling pathways or the timing of their activation/inactivation. We will take experimental approaches in human and guinea pig myometrial cells and tissues that will converge in an understanding of the smooth muscle mechanisms of prematurity and provide one or more therapeutic targets not previously known. Because myometrial quiescence is independent of nitric oxide induced global elevations of cGMP; while the peptide activator of particulate guanylyl cyclase (pGC-Type C) relaxes the myometrium in a cGMP-dependent fashion, we suggest that a conundrum exists in our current understanding of cGMP action in myometrial smooth muscle. We will investigate the hypothesis that the cGMP elevation following activation of pGC exists and acts in a compartment distinct from that of soluble guanylyl cyclase. We propose that myometrial pGC is compartmented to myocyte caveolae and/or lipid-rich membrane rafts and, together with the known ability of PKG to increase the uptake of calcium into sarcoplasmic reticulum, acts via PKG Type II to activate a myosin phosphatase (MP) isozyme containing a leucine zipper that permits its activation by PKGII. This in turn lowers the phosphorylation of the rMLC and thus promotes relaxation of uterine muscle. Relaxation of the myometrium by activators of soluble guanylyl cyclase, while leading to the accumulation of cGMP, does so in a soluble compartment that is not in equilibrium with the lipid-rich signaling domain and does not lead to activation of MP despite activation of PKGI. We propose that cGMP in the soluble compartment of the cell acting via PKGI does not regulate relaxation of myometrial smooth muscle. Exploring our hypotheses in uterine smooth muscle with physiological, biochemical and molecular methods will further our understanding of the regulation of myometrial quiescence. Discovery of the precise and unique nature of myometrial signaling will lead to a better understanding of the regulation of labor and preterm labor and may lead to new therapeutic targets in PTL.