title: Hetero-oligomeric Complex between the G Protein-coupled Estrogen Receptor 1 and the Plasma Membrane Ca2+-ATPase 4b.
abstract: The new G protein-coupled estrogen receptor 1 (GPER/GPR30) plays important roles in many organ systems. The plasma membrane Ca(2+)-ATPase (PMCA) is essential for removal of cytoplasmic Ca(2+) and for shaping the time courses of Ca(2+)-dependent activities. Here, we show that PMCA and GPER/GPR30 physically interact and functionally influence each other. In primary endothelial cells, GPER/GPR30 agonist G-1 decreases PMCA-mediated Ca(2+) extrusion by promoting PMCA tyrosine phosphorylation. GPER/GPR30 overexpression decreases PMCA activity, and G-1 further potentiates this effect. GPER/GPR30 knockdown increases PMCA activity, whereas PMCA knockdown substantially reduces GPER/GPR30-mediated phosphorylation of the extracellular signal-related kinase (ERK1/2). GPER/GPR30 co-immunoprecipitates with PMCA with or without treatment with 17β-estradiol, thapsigargin, or G-1. Heterologously expressed GPER/GPR30 in HEK 293 cells co-localizes with PMCA4b, the main endothelial PMCA isoform. Endothelial cells robustly express the PDZ post-synaptic density protein (PSD)-95, whose knockdown reduces the association between GPER/GPR30 and PMCA. Additionally, the association between PMCA4b and GPER/GPR30 is substantially reduced by truncation of either or both of their C-terminal PDZ-binding motifs. Functionally, inhibition of PMCA activity is significantly reduced by truncation of GPER/GPR30's C-terminal PDZ-binding motif. These data strongly indicate that GPER/GPR30 and PMCA4b form a hetero-oligomeric complex in part via the anchoring action of PSD-95, in which they constitutively affect each other's function. Activation of GPER/GPR30 further inhibits PMCA activity through tyrosine phosphorylation of the pump. These interactions represent cross-talk between Ca(2+) signaling and GPER/GPR30-mediated activities.
authors.affiliation: From the Department of Physiology and Pharmacology, College of Osteopathic Medicine, Des Moines University, Des Moines, Iowa 50312 kim.tran@dmu.edu.
authors.forename: Quang-Kim
authors.initials: QK
authors.lastname: Tran
authors.affiliation: From the Department of Physiology and Pharmacology, College of Osteopathic Medicine, Des Moines University, Des Moines, Iowa 50312.
authors.forename: Mark
authors.initials: M
authors.lastname: VerMeer
authors.affiliation: From the Department of Physiology and Pharmacology, College of Osteopathic Medicine, Des Moines University, Des Moines, Iowa 50312.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Burgard
authors.affiliation: From the Department of Physiology and Pharmacology, College of Osteopathic Medicine, Des Moines University, Des Moines, Iowa 50312.
authors.forename: Ali B
authors.initials: AB
authors.lastname: Hassan
authors.affiliation: From the Department of Physiology and Pharmacology, College of Osteopathic Medicine, Des Moines University, Des Moines, Iowa 50312.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Giles
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine
chemical_list: C109584:GPER1 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium
keywords: G protein-coupled receptor (GPCR); GPER/GPR30; PDZ domain; PMCA4b; PSD-95; endothelium; hetero-oligomeric complex; phosphorylation; plasma membrane calcium-transporting ATPase 4 (ATP2B4)
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