Abstract
Ca2+-permeable channels that are involved in the responses of mammalian cells to changes in extracellular osmolarity have not been characterized at the molecular level. Here we identify a new TRP (transient receptor potential)-like channel protein, OTRPC4, that is expressed at high levels in the kidney, liver and heart. OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity. Changes in osmolarity of as little as 10% result in significant changes in intracellular Ca2+ concentration. We propose that OTRPC4 is a candidate for a molecular sensor that confers osmosensitivity on mammalian cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Colbert, H. A., Smith, T. L. & Bargmann, C. I. Osm-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation and olfactory adaptation in Caenorhabditis elegans. J. Neurosci. 17, 8259–8269 (1997).
Montell, C. & Rubin, G. M. Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron 2, 1313– 1323 (1989).
Harteneck, C., Plant, T. D. & Schultz, G. From worm to man: three subfamilies of TRP channels . Trends Neurosci. 23, 159– 166 (2000).
Phillips, A. M., Bull, A. & Kelly, L. E. Identification of a Drosophila gene encoding a calmodulin-binding protein with homology to the trp phototransduction gene. Neuron 8, 631–642 (1992).
Wes, P. D. et al. TRPC1, a human homolog of a Drosophila store-operated channel. Proc. Natl Acad. Sci. USA 92, 9652 –9656 (1995).
Zhu, X., Chu, P. B., Peyton, M. & Birnbaumer, L. Molecular cloning of a widely expressed human homologue for the Drosophila trp gene. FEBS Lett. 373, 193–198 (1995).
Wissenbach, U., Schroth, G., Phillip, S. & Flockerzi, V. Structure and mRNA expression of a bovine trp homologue related to mammalian trp2. FEBS Lett. 429, 61–66 (1998).
Zhu, X. et al. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 85, 661–671 (1996).
Philipp, S. et al. A mammalian capacitative calcium entry channel homologous to Drosophila TRP and TRPL. EMBO J. 15, 6166–6171 (1996).
Okada, T. et al. Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain. J. Biol. Chem. 273, 10279–10287 (1998).
Philipp, S. et al. A novel capacitative calcium entry channel expressed in excitable cells. EMBO J. 17, 4274– 4282 (1998).
Boulay, G. et al. Cloning and expression of a novel mammalian homologue of Drosophila transient receptor potential (TRP) involved in calcium entry secondary to activation of receptors coupled by the Gq class of G protein. J. Biol. Chem. 272, 29672– 29680 (1997).
Okada, T. et al. Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. J. Biol. Chem. 274, 27359–27370 (1999).
Hofmann, T. et al. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol . Nature 397, 259–263 (1999).
Caterina, M. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816– 824 (1997).
Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531– 543 (1998).
Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. A capsaicin receptor homologue with a high threshold for noxious heat. Nature 398, 436–441 (1999).
Kanzaki, M. et al. Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I. Nature Cell Biol. 1, 165–170 (1999).
Hoenderop, J. G. J. et al. Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J. Biol. Chem. 274, 8375–8378 (1999).
Peng, J. B. et al. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J. Biol. Chem. 274, 22739–22746 (1999).
Schaefer, M. et al. Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J. Biol. Chem. 275, 17517 –17526 (2000).
Thastrup, O., Cullen, P. J., Drøbak, B. K., Hanley, M. R. & Dawson, A. P. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+ ATPase. Proc. Natl Acad. Sci. USA 87, 2466–2470 (1990).
Foskett, J. K. in Cellular and Molecular Physiology of Cell Volume Regulation (ed. Strange, K.) 259–277 (CRC, Boca Raton, 1994).
Nilius, B., Eggermont, J., Voets, T. & Droogmans, G. Volume-activated Cl− channels. Gen. Pharmacol. 27, 1131–1140 (1996).
Suzuki, M., Sato, J., Kutsuwada, K., Ooki, G. & Imai, M. Cloning of a stretch-inhibitable nonselective cation channel. J. Biol. Chem. 274, 6330–6335 (1999).
Walker, R. G., Willingham, A. T. & Zuker, C. S. A Drosophila mechanosensory transduction channel . Science 287, 2229–2234 (2000).
Urbach, V., Leguen, I., O'Kelly, I. & Harvey, B. J. Mechanosensitive calcium entry and mobilization in renal A6 cells. J. Membr. Biol. 168, 29–37 (1999).
Christensen, O. Mediation of cell volume regulation by Ca2+ influx through stretch- activated channels. Nature 330, 66–68 (1987).
Altamirano, J., Brodwick, M. S. & Alvarez-Leefmans, F. J. Regulatory volume decrease and intracellular Ca2+ in murine neuroblastoma cells studied with fluorescent probes. J. Gen. Physiol. 112, 145– 160 (1998).
Voets, T. et al. Regulation of a swelling-activated chloride current in bovine endothelium by protein tyrosine phosphorylation and G proteins. J. Physiol. (Lond.) 506, 341–352 (1998).
Voets, T., Droogmans, G., Raskin, G., Eggermont, J. & Nilius, B. Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels. Proc. Natl Acad. Sci. USA 96, 5298–5303 (1999).
Vennekens, R. et al. Permeation and gating properties of the novel epithelial Ca2+ channel. J. Biol. Chem. 275, 3963–3969 (2000).
Harteneck, C., Obukhov, A. G., Zobel, A., Kalkbrenner, F. & Schultz, G. The Drosophila cation channel trpl expressed in insect Sf9 cells is stimulated by agonists of G-protein-coupled receptors. FEBS Lett. 358, 297– 300 (1995).
Hoenderop, J. G. et al. The epithelial calcium channel, ECaC, is activated by hyperpolarization and regulated by cytosolic calcium. Biochem. Biophys. Res. Commun. 261, 488–492 (1999).
Rothstein, A. & Mack, E. Volume-activated calcium uptake: its role in cell volume regulation of Madin–Darby canine kidney cells. Am. J. Physiol. 262, C339–347 (1992).
Wong, S. M., DeBell, M. C. & Chase, H. S. Jr Cell swelling increases intracellular free [Ca] in cultured toad bladder cells. Am. J. Physiol. 258, F292–296 (1990).
Lang, F. et al. Functional significance of cell volume regulatory mechanisms . Physiol. Rev. 78, 247– 306 (1998).
MacLeod, R. J., Lembessis, P. & Hamilton, J. R. Differences in Ca2+-mediation of hypotonic and Na+-nutrient regulatory volume decrease in suspensions of jejunal enterocytes. J. Membr. Biol. 130, 23–31 (1992).
Kotera, T. & Brown, P. D. Calcium-dependent chloride current activated by hyposmotic stress in rat lacrimal acinar cells. J. Membr. Biol. 134, 67–74 (1993).
Wu, X., Yang, H., Iserovich, P., Fischbarg, J. & Reinach, P. S. Regulatory volume decrease by SV40-transformed rabbit corneal epithelial cells requires ryanodine-sensitive Ca2+-induced Ca2+ release. J. Membr. Biol. 158, 127–136 (1997).
Horn, R. & Marty, A. Muscarinic activation of ionic currents measured by a new whole-cell recording method. J. Gen. Physiol. 92, 145–159 (1988).
Rae, J., Cooper, K., Gates, P. & Watsky, M. Low access resistance perforated patch recordings using amphotericin B. J. Neurosci. Methods 37, 15–26 (1991).
Acknowledgements
We thank M. Schaefer for discussions and I. Reinsch for technical assistance. This work was supported by grants from the DFG and Fonds der Chemischen Industrie.
Correspondence and requests for materials should be addressed to T.D.P. The cDNA sequences encoding the mouse and the human OTRPC4 orthologues have been deposited at GenBank under accession numbers and AF208026, AF258465 respectively.
Author information
Authors and Affiliations
Corresponding author
Additional information
Correspondence and requests for materials should be addressed to T.D.P. The cDNA sequences encoding the mouse and the human OTRPC4 orthologues have been deposited at GenBank under accession numbers AF208026 and AF258465, respectively.
Rights and permissions
About this article
Cite this article
Strotmann, R., Harteneck, C., Nunnenmacher, K. et al. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2, 695–702 (2000). https://doi.org/10.1038/35036318
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/35036318
This article is cited by
-
Molecular details of ruthenium red pore block in TRPV channels
EMBO Reports (2024)
-
Backbone NMR assignments of the extensive human and chicken TRPV4 N-terminal intrinsically disordered regions as important players in ion channel regulation
Biomolecular NMR Assignments (2022)
-
NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels
Basic Research in Cardiology (2022)
-
TRPM7 is an essential regulator for volume-sensitive outwardly rectifying anion channel
Communications Biology (2021)
-
Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)
Nature Communications (2021)