title: Altered permeability and modulatory character of connexin channels during mammary gland development.
abstract: Abrupt developmental changes occur in structural form and function of connexin (Cx) channels in the mouse mammary gland. Microarray study shows that the principal connexin isoform in epithelial cells during pregnancy is Cx26, up-regulated and persisting from the virgin. After parturition, there is rapid induction of Cx32. In epithelial plasma membranes, size exclusion chromatography reveals that Cx32 organizes initially with Cx26 as heteromeric (Cx26-Cx32) hemichannels and later in heteromeric and homomeric Cx32 channels. Dramatic alterations of connexin channel function following these developmental changes in channel composition are characterized using native channels reconstituted into liposomes. Changes to channel stoichiometry increase the allowable physical size limits of permeant after parturition; the new Cx32 channels are wider than channels containing Cx26. Most remarkably, heteromeric Cx26-Cx32 channels are selectively permeability to adenosine 3',5' cyclic phosphate (cAMP), guanosine 3',5' cyclic phosphate (cGMP), and inositol 1,4,5-triphosphate (IP(3)), whereas homomeric channels are not. Homomeric Cx26 and heteromeric channels with high Cx26/Cx32 stoichiometry are also inhibited by taurine, an osmolyte playing a key role in milk protein synthesis. Taurine effect is reduced where heteromeric channels contain Cx32 > Cx26 and eliminated when channels contain only Cx32. Connexin channel stoichiometry, permeability, and chemical gating character change in precisely the desired fashion after parturition to maximize molecular and electrical coupling to support coordinated milk secretion.
authors.affiliation: Department of Pharmacology and Physiology, UMDNJ, Newark, NJ 07101, USA. lockeda@umdnj.edu
authors.forename: Darren
authors.initials: D
authors.lastname: Locke
authors.forename: Torsten
authors.initials: T
authors.lastname: Stein
authors.forename: Claire
authors.initials: C
authors.lastname: Davies
authors.forename: Joanna
authors.initials: J
authors.lastname: Morris
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Harris
authors.forename: W Howard
authors.initials: WH
authors.lastname: Evans
authors.forename: Paul
authors.initials: P
authors.lastname: Monaghan
authors.forename: Barry
authors.initials: B
authors.lastname: Gusterson
mesh_terms: D000328:Adult; D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D000072259:Connexin 26; D017630:Connexins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D017629:Gap Junctions / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007774:Lactation / Q000187:drug effects / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008892:Milk / Q000378:metabolism; D013347:Subcellular Fractions; D013654:Taurine / Q000378:metabolism / Q000494:pharmacology; D000097002:Gap Junction beta-1 Protein
chemical_list: D000072259:Connexin 26; D017630:Connexins; D000242:Cyclic AMP; D006152:Cyclic GMP; D015544:Inositol 1,4,5-Trisphosphate; D013654:Taurine; D000097002:Gap Junction beta-1 Protein; C000607042:GJB2 protein, human