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.
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 Calpha (PKCalpha)-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.
Hawkes
Cheryl
C
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada.
Jhamandas
Jack H
JH
Harris
Kim H
KH
Fu
Wen
W
MacDonald
Richard G
RG
Kar
Satyabrata
S
D000109:Acetylcholine / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive; D002772:Cholera Toxin / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D019922:GAP-43 Protein / Q000502:physiology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000031:analogs & derivatives / Q000235:genetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology; D051571:Protein Kinase C-alpha / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000276:immunology / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D051668:Delayed Rectifier Potassium Channels; D019922:GAP-43 Protein; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D017527:Receptor, IGF Type 2; D043562:Receptors, G-Protein-Coupled; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C067045:insulin-like growth factor II, Leu(27)-; D006165:Guanylyl Imidodiphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C064719:iberiotoxin; D002772:Cholera Toxin; D037342:Pertussis Toxin; D051571:Protein Kinase C-alpha; D051960:GTP-Binding Protein alpha Subunit, Gi2; D007545:Isoproterenol; D000109:Acetylcholine