Membrane Receptor Neighborhoods

A provocative new study in the current issue of Circulation Research by Ibarra et al1 suggests that insulin-like growth factor 1 receptors (IGF-1R) exist in plasma membrane invaginations that come in very close proximity to (or even invade) the nuclear membrane in cardiac myocytes to selectively raise local nuclear [Ca2+]. This article raises an intriguing and novel mechanism by which plasma membrane receptors may have preferential local access to nuclear signaling, even in ventricular myocytes which are large cells with central nuclei.Article, see p 236 The IGF-1R is a tyrosine kinase growth factor receptor that connects with many downstream signaling cascades.2 The 2 best-known pathways are Ras-Raf-mitogen-activated protein kinase and phosphatidylinositide 3 kinase-protein kinase B (Akt). However, Ibarra et al1 focus on a less well-studied pathway in which IGF-1 induces Gi-dependent phospholipase C activation3 and 1,4,5-inositol trisphosphate (InsP3) that can release Ca2+ from intracellular InsP3 receptor (InsP3R) stores.4 They show that in cardiac myocytes IGF-1 triggers nuclear Ca2+ transients that precede cytosolic Ca2+ transients, and that blocking the nuclear Ca2+ transient prevents the cytosolic Ca2+ transient, but not vice versa. Their data are consistent with the idea that a substantial fraction of plasma membrane IGF-R1 are in patches of plasma membrane invaginations that are extremely close to the nucleus, potentially as extensions of the transverse tubule (T-tubule) system. Further, they infer that these IGF-1R are Gi-coupled and that upon activation they produce phospholipase C and InsP3-dependent nuclear Ca2+ transients that contributes to Ca-dependent regulation of gene transcription (Figure B). …