title: Insulin receptor-related receptor as an extracellular alkali sensor.
abstract: 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.
authors.affiliation: Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Deyev
authors.forename: Fabien
authors.initials: F
authors.lastname: Sohet
authors.forename: Konstantin P
authors.initials: KP
authors.lastname: Vassilenko
authors.forename: Oxana V
authors.initials: OV
authors.lastname: Serova
authors.forename: Nadezhda V
authors.initials: NV
authors.lastname: Popova
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Zozulya
authors.forename: Elena B
authors.initials: EB
authors.lastname: Burova
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Rzhevsky
authors.forename: Anastasiya A
authors.initials: AA
authors.lastname: Berchatova
authors.forename: Arkady N
authors.initials: AN
authors.lastname: Murashev
authors.forename: Anton O
authors.initials: AO
authors.lastname: Chugunov
authors.forename: Roman G
authors.initials: RG
authors.lastname: Efremov
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Nikol'sky
authors.forename: Eugenio
authors.initials: E
authors.lastname: Bertelli
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Petrenko
mesh_terms: D000818:Animals; D002460:Cell Line; D003470:Culture Media; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017693:Sodium Bicarbonate / Q000494:pharmacology / Q000652:urine; D014982:Xenopus laevis
chemical_list: D003470:Culture Media; D011993:Recombinant Fusion Proteins; D017693:Sodium Bicarbonate; D011972:Receptor, Insulin; C066542:insulin receptor-related receptor