Activation of store-operated calcium entry in airway smooth muscle cells: insight from a mathematical model.
Intracellular Ca(2+) dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper-responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated Ca(2+) entry (SOCE) in these Ca(2+) dynamics by constructing a mathematical model of ASMC Ca(2+) signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient Ca(2+) depletion of the sarcoplasmic reticulum (SR), while receptor-operated [Ca(2+) entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced Ca(2+) oscillations in the absence of other [Ca(2+) influx. SOCE up-regulation may thus contribute to AHR by increasing the Ca(2+) oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic Ca(2+) of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of Ca(2+). This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC.
School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom.
Huguette
H
Croisier
Xiahui
X
Tan
Jose F
JF
Perez-Zoghbi
Michael J
MJ
Sanderson
James
J
Sneyd
Bindi S
BS
Brook
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008962:Models, Theoretical; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D046509:Tissue Culture Techniques
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007211:Indoles; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C000543:cyclopiazonic acid