PI-PLC FUNCTION IN PREGNANT RAT MYOMETRIUM

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Phosphoinositide-specific phospholipase C (PI-PLC) plays an essential role during intracellular signal transduction in myometrium in response to uterotonic hormones (eg. oxytocin). Recent reports have confirmed that PI- PLC also plays an important role in the development and maintenance of cytosolic calcium oscillations occurring in many different cell types in response to hormone receptor occupancy. As discussed in the preliminary data, studies performed in my laboratory have provided compelling support for the hypothesis t at myometrial contractions occur in response :t,o oxytocin stimulated cytosolic calcium oscillations. This data also suggests that PI-PLC plays an essential role in the biochemical events resulting in cytosolic calcium oscillations and myometrial contractions. The research being proposed in this application will test the hypothesis that oxytocin stimulates the G-protein/PI-PLC complex, resulting in cytosolic calcium oscIllations which drive phasic myometrial contractions. The specific aims are as follows: 1) evaluate the effects of uterotonic agonists and PI-PLC inhibitors on cytosolic calcium oscillations and phasic myometrial contractions, 2) elucidate the role of inositol 1,4,5- trisphosphate during cytosolic calcium oscillations and phasic myometrial contractions, 3) evaluate the role of calcium-induced calcium release (CICR) during PI -PLC induced calcium oscillations and phasic myometrial contractions, and 4) evaluate the role of extracellular calcium during PI- PLC induced calcium oscillations and phasic myometrial contractions. The proposed studies will be performed utilizing myometrial tissue obtained from pregnant Sprague-Dawley rats on specific days of gestation. These studies will provide, for the first time, an intracellular mechanism explaining how oxytocin stimulation results in the development of phasic myometrial contraction.Characterization of these signal transduction mechanisms in myometrium will significantly improve our understanding of basic mechanisms occurring during parturition, and facilitate the development of effective pharmacologic agents to treat disturbances of labor (eg. premature labor).