Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium

Ha, Praetorius; Kr, Spring

doi:10.1007/s00232-001-0075-4

Cited by 747 publications

(695 citation statements)

References 26 publications

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“…However, PKD1 and PKD2-mediated Ca 2+ signaling was independent of PLC activation and inhibited by ryonodine and caffeine [62]. These data were in sharp contrast to the data obtained earlier on cilium-bending and fluid flow-induced Ca 2+ signaling in MDCK cells [55], suggesting that PKD1 and PKD2 modulate Ca 2+ signaling through a completely different signaling mechanism from cilium bending. The reasons for these discrepancies are unknown.…”

Section: Function At the Primary Ciliumcontrasting

confidence: 88%

“…In support of this hypothesis, it has been shown that mechanical bending of the primary cilium or fluid flow in MDCK cells resulted in increases in intracellular Ca 2+ concentration which was dependent on extracellular Ca 2+ , PLC activation and inositol 1,4,5 trisphosphate (IP 3 )-induced release of intracellular Ca 2+ stores [55][56][57]. It is noteworthy that bending-induced Ca 2+ signaling was not affected by inhibition of ryonodine receptors [55]. Several groups have shown the expression of PKD1 and PKD2 in the primary cilium [24,26,58,59].…”

Section: Function At the Primary Ciliummentioning

confidence: 92%

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Cell biology of polycystin-2

Tsiokas¹,

Kim²,

Ong³

2007

Cellular Signalling

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Naturally occurring mutations in two separate, but interacting loci, pkd1 and pkd2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common genetic diseases resulting primarily in the formation of large kidney, liver, and pancreatic cysts. Homozygous deletion of either pkd1 or pkd2 results in embryonic lethality in mice due to kidney and heart defects illustrating their indispensable roles in mammalian development. However, the mechanism by which mutations in these genes cause ADPKD and other developmental defects are unknown. Research in the past several years has revealed that PKD2 has multiple functions depending on its subcellular localization. It forms a receptor-operated, non-selective cation channel in the plasma membrane, a novel intracellular Ca 2+ release channel in the endoplasmic reticulum (ER), and a mechanosensitive channel in the primary cilium. This review focuses on the functional compartmentalization of PKD2, its modes of activation, and PKD2-mediated signal transduction.

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Section: Function At the Primary Ciliumcontrasting

confidence: 88%

Section: Function At the Primary Ciliummentioning

confidence: 92%

Cell biology of polycystin-2

Tsiokas¹,

Kim²,

Ong³

2007

Cellular Signalling

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“…Luminal flow has also been shown to induce a rapid increase in intracellular calcium in renal epithelial cells (41,54). In endothelial cells, eNOS activation by flow is independent of calcium and calcium/calmodulin stimulation (11,12,50), arguing against a role for intracellular calcium in eNOS trafficking and activation in the THAL.…”

Section: Discussionmentioning

confidence: 99%

Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90

Ortíz¹,

Hong²,

Garvin³

2004

American Journal of Physiology-Renal Physiology

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Endothelial nitric oxide synthase (eNOS) regulates NaCl absorption by the thick ascending limb of the loop of Henle (THAL). We found that augmenting luminal flow induces eNOS activation and translocation to the apical membrane of THALs (Ortiz PA, Hong NJ, and Garvin JL. Am J Physiol Renal Physiol 287: F274 -F280, 2004). In other cells, eNOS activation by shear stress is mediated by phosphatidylinositol 3-OH kinase (PI3)-kinase. We hypothesized that luminal flow induces eNOS activation via PI3-kinase. Pretreatment of THALs with wortmannin, a PI3-kinase inhibitor, significantly reduced flow-induced nitric oxide (NO) release by 75% (from 53.6 Ϯ 6 to 13.2 Ϯ 5.7 pA/mm). Increasing luminal flow from 0 to 20 nl/min induced eNOS translocation to the apical membrane, whereas in the presence of wortmannin eNOS translocation was prevented (basolateral ϭ 32 Ϯ 2%, middle ϭ 38 Ϯ 1%, apical ϭ 30 Ϯ 1%, n ϭ 5, not significant vs. no flow). We next studied which PI3-kinase product mediates eNOS translocation. Addition of PI(3,4,5)P 3 (5 M) in the absence of flow increased NO levels (P Ͻ 0.05) and induced eNOS translocation to the apical membrane (from 40 Ϯ 4 to 60 Ϯ 2% of total eNOS, n ϭ 6, P Ͻ 0.05). Incubation with PI(3,4)P 2 or PI(4,5)P2 did not change eNOS localization. We next tested whether heat shock protein (Hsp)90 is involved in eNOS translocation. The Hsp90 inhibitor geldanamycin blocked flow-induced eNOS translocation to the apical membrane (n ϭ 6). Flow also induced translocation of Hsp90 to the apical membrane (from 35 Ϯ 2 to 57 Ϯ 2%; P Ͻ 0.05) in a PI3-kinasedependent manner. We conclude that luminal flow induces eNOS translocation and activation in the THAL via PI3-kinase and that Hsp90 is involved in eNOS translocation to the apical membrane. nitric oxide; renal tubules; trafficking; phosphatidylinositol; heat shock protein; endothelial nitric oxide synthase IN POLARIZED EPITHELIAL CELLS of the kidney, respiratory tract, and testis, nitric oxide (NO) produced by endothelial NO synthase (eNOS) regulates important cellular functions (14,27,29,34,55,57,60). Thus eNOS activity and NO production must be tightly regulated in these cells. We previously reported that NO acts as an autacoid to inhibit NaCl and bicarbonate absorption by the thick ascending limb of the loop of Henle (THAL) (31,32,39). More recently, we identified eNOS as the NOS isoform responsible for the regulation of NaCl absorption by the THAL (35, 38). We recently observed that increasing luminal flow acutely stimulated eNOS activity and induced translocation of eNOS from the basolateral membrane and cytoplasm to the apical membrane of isolated THALs (34a). However, the signaling cascade that mediates eNOS activation and translocation by flow is unknown.Regulation of eNOS has been studied in depth in vascular endothelial cells, where one of the most potent activators of eNOS is flow-induced shear stress (5, 46). The mechanism by which flow activates eNOS in these cells is independent of changes in intracellular calcium and involves activation of the pho...

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“…In mice lacking P2X 4 receptors, flowinduced increases of [Ca 2+ ] i in the endothelial cells were absent, as was the endothelium-dependent vascular dilatation. Flow-induced increases in [Ca 2+ ] i can also be elicited in renal epithelia [130][131][132]. This phenomenon has received much attention as it was hypothesised that an absence of flow sensing in renal epithelia causes polycystic kidney disease [133].…”

Section: Mechanically Released Nucleotidesmentioning

confidence: 99%

ATP release from non-excitable cells

Praetorius

Leipziger

2009

Purinergic Signalling

207

229

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All cells release nucleotides and are in one way or another involved in local autocrine and paracrine regulation of organ function via stimulation of purinergic receptors. Significant technical advances have been made in recent years to quantify more precisely resting and stimulated adenosine triphosphate (ATP) concentrations in close proximity to the plasma membrane. These technical advances are reviewed here. However, the mechanisms by which cells release ATP continue to be enigmatic. The current state of knowledge on different suggested mechanisms is also reviewed. Current evidence suggests that two separate regulated modes of ATP release co-exist in nonexcitable cells: (1) a conductive pore which in several systems has been found to be the channel pannexin 1 and (2) vesicular release. Modes of stimulation of ATP release are reviewed and indicate that both subtle mechanical stimulation and agonist-triggered release play pivotal roles. The mechano-sensor for ATP release is not yet defined.

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Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium

Cited by 747 publications

References 26 publications

Cell biology of polycystin-2

Cell biology of polycystin-2

Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90

ATP release from non-excitable cells

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