title: Calcineurin upregulates local Ca(2+) signaling through ryanodine receptor-1 in airway smooth muscle cells.
abstract: Local Ca(2+) signals (Ca(2+) sparks) play an important role in multiple cellular functions in airway smooth muscle cells (ASMCs). Protein kinase Cϵ is known to downregulate ASMC Ca(2+) sparks and contraction; however, no complementary phosphatase has been shown to produce opposite effects. Here, we for the first time report that treatment with a specific calcineurin (CaN) autoinhibitory peptide (CAIP) to block CaN activity decreases, whereas application of nickel to activate CaN increases, Ca(2+) sparks in both the presence and absence of extracellular Ca(2+). Treatment with xestospogin-C to eliminate functional inositol 1,4,5-trisphosphate receptors does not prevent CAIP from inhibiting local Ca(2+) signaling. However, high ryanodine treatment almost completely blocks spark formation and prevents the nickel-mediated increase in sparks. Unlike CAIP, the protein phosphatase 2A inhibitor endothall has no effect. Local Ca(2+) signaling is lower in CaN catalytic subunit Aα gene knockout (CaN-Aα(-/-)) mouse ASMCs. The effects of CAIP and nickel are completely lost in CaN-Aα(-/-) ASMCs. Neither CAIP nor nickel produces an effect on Ca(2+) sparks in type 1 ryanodine receptor heterozygous knockout (RyR1(-/+)) mouse ASMCs. However, their effects are not altered in RyR2(-/+) or RyR3(-/-) mouse ASMCs. CaN inhibition decreases methacholine-induced contraction in isolated RyR1(+/+) but not RyR1(-/+) mouse tracheal rings. Supportively, muscarinic contractile responses are also reduced in CaN-Aα(-/+) mouse tracheal rings. Taken together, these results provide novel evidence that CaN regulates ASMC Ca(2+) sparks specifically through RyR1, which plays an important role in the control of Ca(2+) signaling and contraction in ASMCs.
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York;
authors.forename: Carlo P
authors.initials: CP
authors.lastname: Savoia
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; Institute for Medical Biology, College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China;
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Liu
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York;
authors.forename: Yun-Min
authors.initials: YM
authors.lastname: Zheng
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York;
authors.forename: Vishal
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Synaptic Transmission Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Synaptic Transmission Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
authors.forename: Ling-Gang
authors.initials: LG
authors.lastname: Wu
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; wangy@mail.amc.edu.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D020013:Calcium Signaling; D002460:Cell Line; D005260:Female; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D065095:Calcineurin Inhibitors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D010455:Peptides; D019837:Ryanodine Receptor Calcium Release Channel; C000592747:ryanodine receptor 1, mouse; C000592748:ryanodine receptor 2. mouse; C511704:xestospongin C; D012433:Ryanodine; D019703:Calcineurin; D054648:Protein Phosphatase 2
keywords: contraction; local calcium signaling