title: Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis.
abstract: The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism.
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut egbert@uchc.edu.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Egbert
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Tracy F
authors.initials: TF
authors.lastname: Uliasz
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Leia C
authors.initials: LC
authors.lastname: Shuhaibar
authors.affiliation: Bayer Pharma AG, Pharma Research Center, Wuppertal, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geerts
authors.affiliation: Bayer Pharma AG, Pharma Research Center, Wuppertal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Wunder
authors.affiliation: Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Kleiman
authors.affiliation: Pfizer Worldwide Research & Development, Groton, Connecticut.
authors.forename: John M
authors.initials: JM
authors.lastname: Humphrey
authors.affiliation: Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lampe
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa.
authors.forename: Nikolai O
authors.initials: NO
authors.lastname: Artemyev
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington.
authors.forename: Sergei D
authors.initials: SD
authors.lastname: Rybalkin
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Beavo
authors.affiliation: Cardiology Section, VA Salt Lake City Health Care System and Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Movsesian
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut ljaffe@uchc.edu.
authors.forename: Laurinda A
authors.initials: LA
authors.lastname: Jaffe
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D005260:Female; D007986:Luteinizing Hormone / Q000494:pharmacology*; D008540:Meiosis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D006080:Ovarian Follicle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007986:Luteinizing Hormone; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP
keywords: cyclic GMP; cyclic nucleotide phosphodiesterase; luteinizing hormone; meiosis; ovarian follicle