Journal
JOURNAL OF CELL SCIENCE
Volume 121, Issue 1, Pages 110-119Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.011692
Keywords
adenylyl cyclase; lung; permeability
Categories
Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL066299, R37HL060024, R01HL060024] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL-60024, P01 HL066299, P01 HL066299-080001, R01 HL060024-10, P01 HL066299-08, HL-66299, R01 HL060024] Funding Source: Medline
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Dynamic cAMP fluctuations that are restricted to a subplasma-membrane domain strengthen endothelial barrier integrity. Phosphodiesterases (PDEs) localize within this domain where they limit cAMP diffusion into the bulk cytosolic compartment; however, the molecular identity of PDEs responsible for endothelial cell membrane cAMP compartmentation remain poorly understood. Our present findings reveal that the D4 splice variant of the PDE4 phosphodiesterase family - PDE4D4 - is expressed in pulmonary microvascular endothelial cells, and is found in plasma membrane fractions. PDE4D4 interacts with alpha II spectrin within this membrane domain. Although constitutive PDE4D4 activity limits cAMP access to the bulk cytosol, inhibiting its activity permits cAMP to access a cytosolic domain that is rich in microtubules, where it promotes protein kinase A (PKA) phosphorylation of tau at Ser214. Such phosphorylation reorganizes microtubules and induces interendothelial cell gap formation. Thus, spectrin-anchored PDE4D4 shapes the physiological response to cAMP by directing it to barrier-enhancing effectors while limiting PKA-mediated microtubule reorganization.
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