Insulin receptor-related receptor (INSRR) (INSRR)

The Insulin receptor-related receptor (INSRR) is a member of the insulin receptor subfamily of receptor tyrosine kinases, which also includes the insulin receptor (INSR) and the insulin-like growth factor 1 receptor (IGF1R) (UniProt P14616). Unlike its homologs, INSRR is an orphan receptor that is not activated by insulin or insulin-like growth factors; instead, it functions as a specific cell surface alkali sensor (Deyev et al., 2011, PMID: 21633350). It is primarily expressed in the intercalated cells of the kidney's collecting ducts, where it responds to extracellular alkaline environments by undergoing autophosphorylation and triggering signaling pathways that promote bicarbonate excretion (Petrenko et al., 2013, PMID: 23836911). This unique physiological role makes INSRR a critical regulator of systemic acid-base homeostasis. While it is not currently a primary target for approved therapeutics, its role in renal pH regulation suggests potential relevance in metabolic alkalosis and certain kidney disorders. Research into small molecule modulators of INSRR is ongoing to explore its potential in managing conditions characterized by acid-base imbalances (Popova et al., 2019, PMID: 31463306).

Other names

IRRInsulin receptor-related proteinProtein tyrosine kinase receptor INSRRIR-related receptor

Activation by extracellular alkaline pH (typically >7.9) induces conformational changes and autophosphorylation of the intracellular kinase domain, which subsequently activates the PI3K/Akt and MAPK/ERK signaling pathways to facilitate renal bicarbonate secretion (Deyev et al., 2011, PMID: 21633350; Petrenko et al., 2013, PMID: 23836911).