Insulin Receptor-Related Receptor as an Extracellular Alkali Sensor

The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-depe...

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Bibliographic Details
Published in:	Cell metabolism Vol. 13; no. 6; pp. 679 - 689
Main Authors:	Deyev, Igor E., Sohet, Fabien, Vassilenko, Konstantin P., Serova, Oxana V., Popova, Nadezhda V., Zozulya, Sergey A., Burova, Elena B., Houillier, Pascal, Rzhevsky, Dmitry I., Berchatova, Anastasiya A., Murashev, Arkady N., Chugunov, Anton O., Efremov, Roman G., Nikol'sky, Nikolai N., Bertelli, Eugenio, Eladari, Dominique, Petrenko, Alexander G.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 08-06-2011
Subjects:	Animals Cell Line Culture Media Humans Hydrogen-Ion Concentration Kidney - drug effects Kidney - metabolism Mice Mice, Inbred C57BL Mice, Knockout Mutagenesis, Site-Directed Phosphorylation Protein Processing, Post-Translational Protein Structure, Tertiary Rats Receptor, Insulin - genetics Receptor, Insulin - metabolism Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Signal Transduction Sodium Bicarbonate - pharmacology Sodium Bicarbonate - urine Xenopus laevis
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Summary:	The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess. ► Insulin receptor-related receptor (IRR) is activated at pH >7.9 ► IRR activation is dose dependent, positively cooperative, and quickly reversible ► IRR pH sensitivity is primarily defined by its L1F extracellular domains ► IRR function in the kidney is coupled to bicarbonate secretion
ISSN:	1550-4131 1932-7420
DOI:	10.1016/j.cmet.2011.03.022