Insulin receptor‐related receptor as an extracellular pH sensor regulating bicarbonate excretion

Abstract

The acid‐base balance in the organism at the system level is controlled primarily by the kidneys and lungs. In the kidneys, this function is performed by the intercalated cells of two types; alpha cells excrete excess acids while beta cells excrete excess bases as bicarbonate. In a result of the biochemical analysis of the insulin receptor‐related receptor (IRR), a receptor‐like tyrosine kinase enriched in beta‐intercalated cells, we discovered its ability to activate upon the extracellular treatment with mildly alkaline media. IRR is a close homolog of the receptors of insulin and insiln‐like growth factor but cannot be activated by to their agonists whereas IRR homologs do not respond to extracellular pH changes. This pH‐sensing property of IRR is evutionary conserved from amphibians to mammals. The IRR activation by alkali resembles a typical ligand‐receptor interaction since it is dose‐dependent and saturable, specific in relation to other homologous receptors, defined by the structure of the IRR ectodomain and accompanied by its conformational changes. Mutagenesis revealed two sites in the IRR ectodomain that act synergystically to induce the receptor activation. IRR activation triggers intracellular signaling resembling the insulin receptor pathway. We obtained a panel of monoclonal antibodies against the IRR ectodomain, one of them being able to activate the receptor, and another – to inhibit its response to alkaline media. Altogether, the obtained data suggest that IRR is a cellular pH sensor. We used kcnockout mice to address IRR systemic functions. The knockout mice are viable in normal conditions but fail to excrete excees bicarbonate upon experimentally induced alkalosis. Nevertheless, the increased blood bicarbonate is compensated by CO2 retention that keeps the blood pH within the physiological range. We performed comparative analyses of knockout and wild type mice kidney and brain transcriptomes and identified statistically valid changes in the expression of several proteins, in particular, ion transporters. Also, a behavioral phenotype of the knockout mice was revealed. They appeared to be less socially active and less agressive as compared to their wild‐type littermates.Support or Funding InformationThis work was financially supported by the Russian Science Foundation (grant № 14‐50‐00131)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.