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Departments of 1 Molecular and Cellular Physiology and 2 Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0576
Sarcoplasmic/endoplasmic reticulum
Ca2+-ATPase 3 (SERCA3), an isoform of the intracellular
Ca2+ pump that has been shown to
mediate endothelium-dependent relaxation of vascular smooth muscle, is
also expressed in tracheal epithelium. To determine its possible role
in regulation of airway mechanical function, we compared tracheal
contractility in gene-targeted mice deficient in SERCA3
(SERCA3
) with that in
wild-type tracheae. Cumulative addition of ACh elicited
concentration-dependent increases in isometric force (ED50 = 2 µM, maximum force = 8 mN/mm2) that were identical in
SERCA3 and wild-type
tracheae. After ACh stimulation, substance P (SP) elicited a transient
relaxation (42.6 ± 3.2%, n = 28)
in both tracheae. However, the rate of relaxation was significantly
(P < 0.04, n = 9) more rapid in the wild-type
[half-time (t1/2) = 34.3 s] than in the SERCA3
(t1/2 = 61.6 s)
trachea. The SP relaxation was reduced by rubbing the trachea,
indicative of epithelial cell involvement. This was verified using a
perfused trachea preparation. SP in the outside medium had no effect,
whereas SP in the perfusate bathing the epithelial side elicited a
relaxation. Nitric oxide synthase inhibition (0.2 mM
N
-nitro-L-arginine) reduced the
SP relaxation by 36.5 ± 12.5%, whereas the SP effect was abolished
by eicosanoid inhibition (10 µM indomethacin). ATP also elicited an
epithelium-dependent relaxation similar to SP but with a more rapid
relaxation in the SERCA3
trachea than in the wild-type trachea. Our results indicate that SERCA3
gene ablation does not directly affect smooth muscle, which is
consistent with the distribution of the isoform, but suggest that
SERCA3 plays a role in epithelial cell modulation of airway smooth
muscle function.
sarcoplasmic/endoplasmic reticulum calcium ion-adenosinetriphosphatase 3; calcium ion-adenosinetriphosphatase; endoplasmic reticulum; substance P; adenosine triphosphate
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