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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/L26    most recent 00026.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Google Scholar Articles by Sathish, V. Articles by Sieck, G. C. PubMed PubMed Citation Articles by Sathish, V. Articles by Sieck, G. C.

Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca²⁺ reuptake in human airway smooth muscle

Departments of ¹Physiology and Biomedical Engineering and ²Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 23 January 2009 ; accepted in final form 22 April 2009

Airway inflammation leads to increased intracellular Ca²⁺ ([Ca²⁺]_i) levels in airway smooth muscle (ASM) cells. Sarcoplasmic reticulum Ca²⁺ release and reuptake are key components of ASM [Ca²⁺]_i regulation. Ca²⁺ reuptake occurs via sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA) and is regulated by the inhibitory protein phospholamban (PLB) in many cell types. In human ASM, we tested the hypothesis that inflammation increases PLB, thus inhibiting SERCA function, and leading to maintained [Ca²⁺]_i levels. Surprisingly, we found that human ASM does not express PLB protein (although mRNA is detectable). Overnight exposure to the proinflammatory cytokines TNF and IL-13 did not induce PLB expression, raising the issue of how SERCA is regulated. We then found that direct SERCA phosphorylation (via CaMKII) occurs in human ASM. In fura-2-loaded human ASM cells, we found that the CaMKII antagonist KN-93 significantly slowed the rate of fall of [Ca²⁺]_i transients induced by ACh or bradykinin (in zero extracellular Ca²⁺), suggesting a role for CaMKII-mediated SERCA regulation. SERCA expression was decreased by cytokine exposure, and the rate of fall of [Ca²⁺]_i transients was slowed in cells exposed to TNF and IL-13. Cytokine effects on Ca²⁺ reuptake were unaffected by additional exposure to KN-93. These data indicate that in human ASM, SERCA is regulated by mechanisms such as CaMKII and that airway inflammation maintains [Ca²⁺]_i levels by decreasing SERCA expression and slowing Ca²⁺ reuptake.

sarcoendoplasmic reticulum Ca²⁺ ATPase; calmodulin; calmodulin kinase; tumor necrosis factor-; interleukin-13

This article has been cited by other articles:

				Y. S. Prakash, V. Sathish, M. A. Thompson, C. M. Pabelick, and G. C. Sieck Asthma and sarcoplasmic reticulum Ca2+ reuptake in airway smooth muscle Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L794 - L794. [Full Text] [PDF]