Different ligand affinities of the two human insulin receptor splice variants are reflected in parallel changes in sensitivity for insulin action.
The human insulin receptor (hIR) is expressed in two variant forms that are generated by tissue-specific alternative splicing of the 11th exon of the IR gene. This leads to receptors that differ in their affinities for insulin based on the absence (hIR-A) or presence (hIR-B) of a 12-amino acid insert near the C-terminus of the alpha-subunit. To explore further the functional significance of the difference in these receptor subtypes, the properties of hIR-A(exon 11-) and hIR-B(exon 11+) receptors have been compared in parallel. Despite their different affinities for insulin, the receptor variants retain equivalent acid sensitivity for insulin binding and bind proinsulin with the same relative affinity. Both hIR-A and hIR-B are able to signal a variety of insulin's actions, but the insulin dose-response curves for receptor autophosphorylation and for mitogenesis and glycogen synthase stimulation in cells are shifted to the right for hIR-B receptors compared to hIR-A receptors. The magnitude of these rightward shifts, 1.5- to 3-fold in the assays listed above, are similar to and presumably accounted for by the 2-fold difference in insulin affinity exhibited by the receptor variants. Occupied hIR-A and hIR-B receptors undergo indistinguishable endocytotic itineraries after insulin binding. Both lead to insulin degradation that is quantitatively and kinetically similar, and both down-regulate when exposed to saturating insulin for 24 h. Thus, the functional consequences of the alternative splicing of IRs are limited to those related to the variants' differing affinities for insulin.
McClain
D A
DA
Division of Endocrinology, University of Alabama, Birmingham.
D000818:Animals; D002999:Clone Cells / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; D012333:RNA, Messenger; D011972:Receptor, Insulin