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ABSTRACT: Ca(2+) is an important signalling molecule that regulates multiple cellular processes, including apoptosis. Although Ca(2+) influx through transient receptor potential (TRP) channels in the plasma membrane is known to trigger cell death, the function of intracellular TRP proteins in the regulation of Ca(2+)-dependent signalling pathways and apoptosis has remained elusive. Here, we show that TRPP2, the ion channel mutated in autosomal dominant polycystic kidney disease (ADPKD), protects cells from apoptosis by lowering the Ca(2+) concentration in the endoplasmic reticulum (ER). ER-resident TRPP2 counteracts the activity of the sarcoendoplasmic Ca(2+) ATPase by increasing the ER Ca(2+) permeability. This results in diminished cytosolic and mitochondrial Ca(2+) signals upon stimulation of inositol 1,4,5-trisphosphate receptors and reduces Ca(2+) release from the ER in response to apoptotic stimuli. Conversely, knockdown of TRPP2 in renal epithelial cells increases ER Ca(2+) release and augments sensitivity to apoptosis. Our findings indicate an important function of ER-resident TRPP2 in the modulation of intracellular Ca(2+) signalling, and provide a molecular mechanism for the increased apoptosis rates in ADPKD upon loss of TRPP2 channel function.
The EMBO Journal 02/2009; 28(5):490-9. · 9.20 Impact Factor
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Michael Köttgen,
Björn Buchholz,
Miguel A Garcia-Gonzalez,
Fruzsina Kotsis,
Xiao Fu,
Mara Doerken,
Christopher Boehlke,
Daniel Steffl, Robert Tauber,
Tomasz Wegierski,
Roland Nitschke,
Makoto Suzuki,
Albrecht Kramer-Zucker,
Gregory G Germino,
Terry Watnick,
Jean Prenen,
Bernd Nilius,
E Wolfgang Kuehn,
Gerd Walz
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ABSTRACT: The primary cilium has evolved as a multifunctional cellular compartment that decorates most vertebrate cells. Cilia sense mechanical stimuli in various organs, but the molecular mechanisms that convert the deflection of cilia into intracellular calcium transients have remained elusive. Polycystin-2 (TRPP2), an ion channel mutated in polycystic kidney disease, is required for cilia-mediated calcium transients but lacks mechanosensitive properties. We find here that TRPP2 utilizes TRPV4 to form a mechano- and thermosensitive molecular sensor in the cilium. Depletion of TRPV4 in renal epithelial cells abolishes flow-induced calcium transients, demonstrating that TRPV4, like TRPP2, is an essential component of the ciliary mechanosensor. Because TRPV4-deficient zebrafish and mice lack renal cysts, our findings challenge the concept that defective ciliary flow sensing constitutes the fundamental mechanism of cystogenesis.
The Journal of General Physiology 10/2008; 132(3):i2. · 3.84 Impact Factor
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Michael Köttgen,
Björn Buchholz,
Miguel A. Garcia-Gonzalez,
Fruzsina Kotsis,
Xiao Fu,
Mara Doerken,
Christopher Boehlke,
Daniel Steffl, Robert Tauber,
Tomasz Wegierski,
Roland Nitschke,
Makoto Suzuki,
Albrecht Kramer-Zucker,
Gregory G. Germino,
Terry Watnick,
Jean Prenen,
Bernd Nilius,
E. Wolfgang Kuehn,
Gerd Walz
[show abstract]
[hide abstract]
ABSTRACT: The primary cilium has evolved as a multifunctional cellular compartment that decorates most vertebrate cells. Cilia sense
mechanical stimuli in various organs, but the molecular mechanisms that convert the deflection of cilia into intracellular
calcium transients have remained elusive. Polycystin-2 (TRPP2), an ion channel mutated in polycystic kidney disease, is required
for cilia-mediated calcium transients but lacks mechanosensitive properties. We find here that TRPP2 utilizes TRPV4 to form
a mechano- and thermosensitive molecular sensor in the cilium. Depletion of TRPV4 in renal epithelial cells abolishes flow-induced
calcium transients, demonstrating that TRPV4, like TRPP2, is an essential component of the ciliary mechanosensor. Because
TRPV4-deficient zebrafish and mice lack renal cysts, our findings challenge the concept that defective ciliary flow sensing
constitutes the fundamental mechanism of cystogenesis.
The Journal of Cell Biology 08/2008; 182(3):437-447. · 10.26 Impact Factor
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Michael Köttgen,
Thomas Benzing,
Thomas Simmen, Robert Tauber,
Björn Buchholz,
Sylvain Feliciangeli,
Tobias B Huber,
Bernhard Schermer,
Albrecht Kramer-Zucker,
Katja Höpker,
Katia Carmine Simmen,
Christoph Carl Tschucke,
Richard Sandford,
Emily Kim,
Gary Thomas,
Gerd Walz
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ABSTRACT: The trafficking of ion channels to the plasma membrane is tightly controlled to ensure the proper regulation of intracellular ion homeostasis and signal transduction. Mutations of polycystin-2, a member of the TRP family of cation channels, cause autosomal dominant polycystic kidney disease, a disorder characterized by renal cysts and progressive renal failure. Polycystin-2 functions as a calcium-permeable nonselective cation channel; however, it is disputed whether polycystin-2 resides and acts at the plasma membrane or endoplasmic reticulum (ER). We show that the subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2, two adaptor proteins that recognize an acidic cluster in the carboxy-terminal domain of polycystin-2. Binding to these adaptor proteins is regulated by the phosphorylation of polycystin-2 by the protein kinase casein kinase 2, required for the routing of polycystin-2 between ER, Golgi and plasma membrane compartments. Our paradigm that polycystin-2 is sorted to and active at both ER and plasma membrane reconciles the previously incongruent views of its localization and function. Furthermore, PACS proteins may represent a novel molecular mechanism for ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.
The EMBO Journal 03/2005; 24(4):705-16. · 9.20 Impact Factor
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ABSTRACT: Ca(2+) influx across the plasma membrane after stimulation of G protein-coupled receptors is important for many physiological functions. Here we studied the regulation of an inwardly rectifying whole cell current and its putative role in Ca(2+) entry in Xenopus oocytes. Expression of P2Y(1) or M1 receptors in Xenopus oocytes elicited a characteristic inwardly rectifying current without receptor stimulation. This current displayed distinct activation and inactivation kinetics and was highly Ca(2+)-dependent. After stimulation of endogenous G(q)-coupled receptors in water-injected cells similar currents were observed. We therefore speculated that the current could be activated via Ca(2+) store depletion induced by constitutive stimulation of the IP(3) cascade in cells overexpressing G(q)-coupled receptors. Receptor-independent Ca(2+) store depletion also induced the current. In conclusion, this current is activated after store depletion suggesting a role in Ca(2+) entry after stimulation of G(q)-coupled receptors. Finally, our data do not support the proposed ionotropic properties of the P2Y(1) receptor.
Biochemical and Biophysical Research Communications 10/2004; 322(1):177-85. · 2.48 Impact Factor
