Although temporally related to the near term fall in progesterone (Pr) and rise in estradiol (E2) observed in the pregnant rat, the hormonal control for the loss of beta adrenergic responsiveness and modulation of beta-2 adrenergic receptor (B2AR) signal transduction events observed near term in the pregnant rat are unknown at this time. The proposed experiments will test the hypothesis that E2 and/or Pr regulate beta-2 adrenergic responsiveness by directly effecting B2AR expression and/or B2AR signal transduction mechanisms. This hypothesis will be tested in a systematic fashion using rat myometrial tissue obtained during normal gestation, myometrial tissue obtained from pregnant rats undergoing steroid hormone manipulation in vivo, and cultured rat uterine myocytes directly stimulated in vitro with steroid hormones. This revised, competitive renewal research grant application is to evaluate the effects of gestation and steroid hormones on: 1) the expression of myometrial beta-2 adrenergic receptors utilizing radioligand binding studies and Northern blots, 2) guanine nucleotide regulatory protein (Gs) function, Gs-alpha subunit MRNA levels, and protein expression, 3) adenylate cyclase (AC) activity, AC MRNA levels, and protein expression, and 4) protein kinase A (CAMP-dependent protein kinase) activity, myocyte PKA target peptides, PKA MRNA levels, and protein expression. The proposed studies will further characterize adrenergic signal transduction mechanisms in pregnant myometrial tissue, with particular emphasis on the elucidation of those events regulated by these steroid hormones as parturition approaches.
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