Insulin Receptor-Related Receptor as an Extracellular Alkali Sensor

Abstract

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, 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.

Structural Determinants of the Insulin Receptor-related Receptor Activation by Alkali

“…Moreover, multiyear studies failed to discover any IRR agonist of the protein or peptide nature. Unexpectedly, recent studies revealed an unusual property of IRR to respond to an increase of extracellular medium pH (5,6). This finding suggests that the hydroxyl anion may represent a natural agonist of IRR (7).…”

“…BC117172) with full or partial ectodomain swapping were obtained by cloning using PCR strategy as described in Ref. 5. For generation of additional constructions with point mutations or with tyrosine kinase domain swapping, we used megaprimer PCR approach with mutated oligonucleotides.…”

“…The physiological importance of IRR as a component of the acid-base homeostasis machinery is supported by complementary in vitro and in vivo studies (5,8). First, unlike its ubiquitously distributed homologs IR and IGF-IR, IRR is located in only specific cell sets within some tissues that come in contact with extracorporeal fluids of extreme pH such as kidney, pancreas, and stomach, as reviewed in Ref.…”

“…The qualitative analysis of IR/IRR chimeras revealed involvement of several extracellular domains in IRR alkali sensing with the primary role of L1C domains (5). To get further insight into the mechanism of IRR activation, we have now developed an in vitro assay of IRR autophosphorylation that could be quantitated.…”

“…Second, in transfected cells, IRR (but not IR or IGF-IR) can be activated by external application of mildly alkaline medium independently of its ionic composition, and this effect is dose-dependent (5). Third, IRR knock-out mice, seemingly healthy under standard environmental conditions, fail to respond properly to an experimentally introduced alkali challenge by kidney secretion of excessive base as bicarbonate (5,8). Thus, the knock-out animal data provide a strong support that the in vitro findings of alkalidependent IRR activation are physiologically relevant.…”