Single transmembrane domain insulin-like growth factor-II/mannose-6- phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway

Hawkes, Cheryl; Jhamandas, Jack H.; Harris, Kim H.; Fu, Wen; MacDonald, Richard G. and Kar, Satyabrata (2006). Single transmembrane domain insulin-like growth factor-II/mannose-6- phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. Journal of Neuroscience, 26(2) pp. 585–596.

DOI: https://doi.org/10.1523/JNEUROSCI.2730-05.2006

Abstract

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a single-pass transmembrane glycoprotein that plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of IGF-II. However, its role in signal transduction after IGF-II binding remains unclear. In the present study, we report that IGF-II/M6P receptor in the rat brain is coupled to a G-protein and that its activation by Leu²⁷IGF-II, an analog that binds rather selectively to the IGF-II/M6P receptor, potentiates endogenous acetylcholine release from the rat hippocampal formation. This effect is mediated by a pertussis toxin (PTX)-sensitive GTP-binding protein and is dependent on protein kinase Cα(PKCα)-induced phosphorylation of downstream substrates, myristoylated alanine-rich C kinase substrate, and growth associated protein-43. Additionally, treatment with Leu²⁷IGF-II causes a reduction in whole-cell currents and depolarization of cholinergic basal forebrain neurons. This effect, which is blocked by an antibody against the IGF-II/M6P receptor, is also sensitive to PTX and is mediated via activation of a PKC-dependent pathway. These results together revealed for the first time that the single transmembrane domain IGF-II/M6P receptor expressed in the brain is G-protein coupled and is involved in the regulation of central cholinergic function via the activation of specific intracellular signaling cascades.

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