Recombinant human insulin-like growth factor I exerts a trophic action and confers glutamate sensitivity on glutamate-resistant cerebellar granule cells.
Cerebellar granule cells grown in the presence of a serum complex differentiate but are resistant to the lethal action of excitatory amino acids. When these cells are grown also in the presence of insulin-like growth factor I (IGF-I) they become fully susceptible to the toxic, lethal action of glutamate. The glutamate-sensitizing action of IGF-I is dependent on concentration (half-maximal effect at 2-4 ng/ml) and time (half-maximal effect at 2-4 days in vitro) and is paralleled by the appearance of functionally active, glutamate-activated, Ca2+ channels and of voltage-gated Na+ and late K+ channels. IGF-I-induced glutamate sensitivity is rapidly reversible (t1/2 = 30-60 min) after removal of this somatomedin. The action of IGF-I is not mimicked by IGF-II, nerve growth factor, basic or acidic fibroblast growth factor, platelet-derived growth factor, or tumor necrosis factor alpha. We postulate that the constitutive phenotype of cerebellar granule cells is glutamate-resistant and becomes responsive to excitatory amino acids under the action of epigenetic cues among which IGF-I may be one of those operative in vivo.
Calissano
P
P
Institute of Neurobiology, Consiglio Nazionale delle Richerche, Rome, Italy.
Ciotti
M T
MT
Battistini
L
L
Zona
C
C
Angelini
A
A
Merlo
D
D
Mercanti
D
D
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D006133:Growth Substances / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D015220:Calcium Channels; D005971:Glutamates; D006133:Growth Substances; D009498:Neurotoxins; D015221:Potassium Channels; D011994:Recombinant Proteins; D015222:Sodium Channels; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D016291:Dizocilpine Maleate; D002118:Calcium