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Am J Physiol Renal Physiol 294: F1279-F1286, 2008. First published April 16, 2008; doi:10.1152/ajprenal.00348.2007
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TRANSLATIONAL PHYSIOLOGY

Heterologous expression of polycystin-1 inhibits endoplasmic reticulum calcium leak in stably transfected MDCK cells

Kimberly H. Weber,1 Eun Kyung Lee,1 Uma Basavanna,1 Sabina Lindley,1 Roy C. Ziegelstein,2 Gregory G. Germino,1 and Michael Sutters1

Departments of 1Nephrology and 2Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 25 July 2007 ; accepted in final form 5 April 2008

We previously found that polycystin-1 accelerated the decay of ligand-activated cytoplasmic calcium transients through enhanced reuptake of calcium into the endoplasmic reticulum (ER; Hooper KM, Boletta A, Germino GG, Hu Q, Ziegelstein RC, Sutters M. Am J Physiol Renal Physiol 289: F521–F530, 2005). Calcium flux across the ER membrane is determined by the balance of active uptake and passive leak. In the present study, we show that polycystin-1 inhibited calcium leak across the ER membrane, an effect that would explain the capacity of this protein to accelerate clearance of calcium from the cytoplasm following a calcium release response. Calcium leak was detected by measurement of the accumulation of calcium in the cytoplasm following treatment with thapsigargin. Heterologous polycystin-1, stably expressed in Madin-Darby canine kidney cells, attenuated the thapsigargin-induced calcium peak with no effect on basal calcium stores, mitochondrial calcium uptake, or extrusion of calcium across the plasma membrane. The capacity of polycystin-1 to limit the rate of decay of ER luminal calcium following inhibition of the pump was shown indirectly using the calcium ionophore ionomycin, and directly by loading the ER with a low-affinity calcium indicator. We conclude that disruption of ER luminal calcium homeostasis may contribute to the cyst phenotype in autosomal dominant polycystic kidney disease.

cell calcium; thapsigargin; autosomal dominant polycystic kidney disease; Madin-Darby canine kidney cells


Address for reprint requests and other correspondence: M. Sutters, Rm. B2N, Div. of Renal Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave., Baltimore, MD 21224 (e-mail: msutters{at}jhmi.edu)






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