title: Essential role of Orai1 store-operated calcium channels in lactation.
abstract: The nourishment of neonates by nursing is the defining characteristic of mammals. However, despite considerable research into the neural control of lactation, an understanding of the signaling mechanisms underlying the production and expulsion of milk by mammary epithelial cells during lactation remains largely unknown. Here we demonstrate that a store-operated Ca(2+) channel subunit, Orai1, is required for both optimal Ca(2+) transport into milk and for milk ejection. Using a novel, 3D imaging strategy, we visualized live oxytocin-induced alveolar unit contractions in the mammary gland, and we demonstrated that in this model milk is ejected by way of pulsatile contractions of these alveolar units. In mammary glands of Orai1 knockout mice, these contractions are infrequent and poorly coordinated. We reveal that oxytocin also induces a large transient release of stored Ca(2+) in mammary myoepithelial cells followed by slow, irregular Ca(2+) oscillations. These oscillations, and not the initial Ca(2+) transient, are mediated exclusively by Orai1 and are absolutely required for milk ejection and pup survival, an observation that redefines the signaling processes responsible for milk ejection. These findings clearly demonstrate that Ca(2+) is not just a substrate for nutritional enrichment in mammals but is also a master regulator of the spatiotemporal signaling events underpinning mammary alveolar unit contraction. Orai1-dependent Ca(2+) oscillations may represent a conserved language in myoepithelial cells of other secretory epithelia, such as sweat glands, potentially shedding light on other Orai1 channelopathies, including anhidrosis (an inability to sweat).
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: Felicity M
authors.initials: FM
authors.lastname: Davis
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: Agnes
authors.initials: A
authors.lastname: Janoshazi
authors.affiliation: Integrated Laboratory Systems, Inc., Research Triangle Park, NC 27709;
authors.forename: Kyathanahalli S
authors.initials: KS
authors.lastname: Janardhan
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: Natacha
authors.initials: N
authors.lastname: Steinckwich
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: Diane M
authors.initials: DM
authors.lastname: D'Agostin
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: John G
authors.initials: JG
authors.lastname: Petranka
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: Pooja N
authors.initials: PN
authors.lastname: Desai
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; and.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Bird
authors.affiliation: National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Deirdre K
authors.initials: DK
authors.lastname: Tucker
authors.affiliation: National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Fenton
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; and.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
authors.affiliation: Department of Health and Human Services, Signal Transduction Laboratory and putney@niehs.nih.gov.
authors.forename: James W
authors.initials: JW
authors.lastname: Putney
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D021621:Imaging, Three-Dimensional; D007477:Ions / Q000737:chemistry; D007774:Lactation; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008892:Milk / Q000378:metabolism; D000071740:ORAI1 Protein; D009991:Oscillometry; D010121:Oxytocin / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D015220:Calcium Channels; D007477:Ions; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D010121:Oxytocin; D002118:Calcium
keywords: calcium channels; calcium signaling; lactation; mammary gland; store-operated calcium entry