Insulin receptor isoform A (IR-A) (IR-A)

The insulin receptor isoform A (IR-A) is a transmembrane receptor tyrosine kinase encoded by the INSR gene, distinguished by the exclusion of exon 11 through alternative splicing [UniProt P06213]. While the IR-B isoform is the primary mediator of glucose homeostasis in peripheral metabolic tissues, IR-A is the predominant isoform expressed in the central nervous system and during embryonic development [PMID: 11518806]. In the brain, IR-A signaling is vital for cognitive functions, including memory consolidation and synaptic plasticity, and provides neuroprotective effects against apoptosis [PMID: 25231861]. Beyond insulin, IR-A serves as a high-affinity receptor for insulin-like growth factor 2 (IGF-2), a property that links it to both normal brain development and the progression of certain malignancies [PMID: 10364463]. Pathologically, reduced IR-A sensitivity or expression in the brain is a hallmark of Alzheimer's disease, often referred to as 'type 3 diabetes' [PMID: 22406071]. Therapeutic strategies targeting IR-A include the use of intranasal insulin to improve cognitive outcomes and the engineering of 'Trojan horse' antibodies that exploit the receptor's transport mechanisms to deliver therapeutics across the blood-brain barrier [PMID: 21832669].

Other names

INSR-AInsulin receptor short isoformIR-shortCD220Exon 11-minus insulin receptor

Activation of the intracellular tyrosine kinase domain upon ligand binding, leading to autophosphorylation and recruitment of insulin receptor substrates (IRS-1/2) to trigger PI3K/Akt and MAPK/ERK signaling pathways [PMID: 25231861]. It also facilitates the transport of ligands and conjugated molecules across the blood-brain barrier via receptor-mediated transcytosis [PMID: 21832669].