▪ Abstract The primary cilium, an organelle largely ignored by physiologists, functions both as a mechano-sensor and a chemo-sensor in renal tubular epithelia. This forgotten structure is critically involved in the determination of left-right sidedness during development and is a key factor in the development of polycystic kidney disease, as well as a number of other abnormalities. This review provides an update of our current understanding about the function of primary cilia. Much new information obtained in the past five years has been stimulated, in part, by discoveries of the primary cilium's key role in the genesis of polycystic kidney disease as well as its involvement in determination of left-right axis asymmetry. Here we focus on the various functions of the primary cilium rather than on its role in pathology.

To discuss recent reports on the function and importance of the renal primary cilium, a widely distributed organelle. Most epithelial cells, including those in the kidney, express a solitary primary cilium. The primary cilium functions as a flow sensor in cultured renal epithelial cells (MDCK and mouse collecting tubule) mediating a large increase in intracellular calcium concentration. Flow sensing is shown to reside in the cilium itself and to involve the proteins polycystin 1 and 2, defects in which are associated with the majority of cases of human polycystic kidney disease. The role of the cilium in flow-dependent potassium secretion by the collecting tubule and in sensing of chemical components of the luminal fluid are also described. The primary cilium is mechanically sensitive and serves as a flow sensor in cultured renal epithelia. Bending the cilium by mechanical means or flow causes a large, prolonged transient increase in intracellular calcium. The mechanically sensitive protein in the cilium is a polycystin.

Calcium (Ca²⁺) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca²⁺-ATPase (SERCA), disrupts Ca²⁺ homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μm) concentrations of Tg and Tg analogs with various long-chain substitutions at the O-8 position extensively inhibit SERCA1a-mediated Ca²⁺ transport. We also found that, in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca²⁺ stores. This Ca²⁺ depletion was followed by markedly reduced cell proliferation rates and morphological changes that developed over 2–4 days and culminated in cell death. Interestingly, these changes were not accompanied by bulk increases in cytosolic Ca²⁺ levels. Moreover, knockdown of two key store-operated Ca²⁺ entry (SOCE) components, Orai1 and STIM1, did not reduce Tg cytotoxicity, indicating that SOCE and Ca²⁺ entry are not critical for Tg-induced cell death. However, we observed a correlation between the abilities of Tg and Tg analogs to deplete ER Ca²⁺ stores and their detrimental effects on cell viability. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response. We conclude that ER Ca²⁺ drainage and sustained unfolded protein response activation are key for initiation of apoptosis at low concentrations of Tg and Tg analogs, whereas high cytosolic Ca²⁺ levels and SOCE are not required.