| First Author | Savoia CP | Year | 2014 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 307 |
| Issue | 10 | Pages | L781-90 |
| PubMed ID | 25239916 | Mgi Jnum | J:222192 |
| Mgi Id | MGI:5644109 | Doi | 10.1152/ajplung.00149.2014 |
| Citation | Savoia CP, et al. (2014) Calcineurin upregulates local Ca(2+) signaling through ryanodine receptor-1 in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 307(10):L781-90 |
| abstractText | Local Ca(2+) signals (Ca(2+) sparks) play an important role in multiple cellular functions in airway smooth muscle cells (ASMCs). Protein kinase C 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 Aalpha gene knockout (CaN-Aalpha(-/-)) mouse ASMCs. The effects of CAIP and nickel are completely lost in CaN-Aalpha(-/-) 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-Aalpha(-/+) 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. |
