Essential role of Orai1 store-operated calcium channels in lactation

Davis, Felicity M., Janoshazi, Agnes, Janardhan, Kyathanahalli S., Steinckwich, Natacha, D'Agostin, Diane M., Petranka, John G., Desai, Pooja N., Roberts-Thomson, Sarah J., Bird, Gary S., Tucker, Deirdre K., Fenton, Suzanne E., Feske, Stefan, Monteith, Gregory R. and Putney, James W. (2015) Essential role of Orai1 store-operated calcium channels in lactation. Proceedings of the National Academy of Sciences of the United States of America, 112 18: 5827-5832. doi:10.1073/pnas.1502264112


Author Davis, Felicity M.
Janoshazi, Agnes
Janardhan, Kyathanahalli S.
Steinckwich, Natacha
D'Agostin, Diane M.
Petranka, John G.
Desai, Pooja N.
Roberts-Thomson, Sarah J.
Bird, Gary S.
Tucker, Deirdre K.
Fenton, Suzanne E.
Feske, Stefan
Monteith, Gregory R.
Putney, James W.
Title Essential role of Orai1 store-operated calcium channels in lactation
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 1091-6490
0027-8424
Publication date 2015-05-05
Year available 2015
Sub-type Article (original research)
DOI 10.1073/pnas.1502264112
Open Access Status Not yet assessed
Volume 112
Issue 18
Start page 5827
End page 5832
Total pages 6
Place of publication Washington, DC United States
Publisher National Academy of Sciences
Language eng
Subject 1000 General
2700 Medicine
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 Ca2+ channel subunit, Orai1, is required for both optimal Ca2+ 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 Ca2+ in mammary myoepithelial cells followed by slow, irregular Ca2+ oscillations. These oscillations, and not the initial Ca2+ 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 Ca2+ 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 Ca2+ 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).
Formatted 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 Ca2+ channel subunit, Orai1, is required for both optimal Ca2+ 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 Ca2+ in mammary myoepithelial cells followed by slow, irregular Ca2+ oscillations. These oscillations, and not the initial Ca2+ 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 Ca2+ 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 Ca2+ 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).
Keyword Calcium signaling
Calcium channels
Lactation
Mammary gland
Store-operated calcium entry
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID AI097302
631347
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Pharmacy Publications
 
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