Abstract
Insulin-like growth factor 1 (IGF-1) rapidly potentiates N and L calcium channel currents in cerebellar granule neurons by an unknown mechanism. Here, we show that the L channel alpha1C subunit is tyrosine phosphorylated in response to IGF-1. Moreover, expression of kinase-dead c-Src in neurons or acute block of Src family kinases with a cell-permeable inhibitor specifically blocks L channel potentiation. Purified Src kinase phosphorylates tyrosine residue Y2122 of the C terminus of neuronal alpha1C in vitro, and c- and v-Src directly bind the C terminus. When expressed in neuroblastoma cells, point mutation of Y2122 prevents both tyrosine phosphorylation of alpha1C and IGF-1 potentiation. Our data provide a biochemical mechanism whereby phosphorylation of a single specific tyrosine residue rapidly modifies ion channel physiology.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium Channel Agonists / pharmacology*
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Calcium Channels, L-Type / drug effects
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Calcium Channels, L-Type / genetics
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Calcium Channels, L-Type / physiology*
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Catalysis
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Cell Line
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Genetic Vectors
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Immunoblotting
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Insulin-Like Growth Factor I / pharmacology*
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Mutagenesis, Site-Directed
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects*
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Patch-Clamp Techniques
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Phosphorus Radioisotopes
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Phosphotyrosine / biosynthesis
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Phosphotyrosine / genetics
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Phosphotyrosine / physiology*
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Precipitin Tests
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Rats
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Stimulation, Chemical
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Tyrosine / genetics
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Tyrosine / physiology*
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src-Family Kinases / metabolism
Substances
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Calcium Channel Agonists
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Calcium Channels, L-Type
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Nerve Tissue Proteins
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Phosphorus Radioisotopes
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Phosphotyrosine
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Tyrosine
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Insulin-Like Growth Factor I
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Proto-Oncogene Proteins pp60(c-src)
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src-Family Kinases