Potentiation of neuronal L calcium channels by IGF-1 requires phosphorylation of the alpha1 subunit on a specific tyrosine residue

Neuron. 2000 Jul;27(1):121-31. doi: 10.1016/s0896-6273(00)00014-3.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium Channel Agonists / pharmacology*
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / physiology*
  • Catalysis
  • Cell Line
  • Genetic Vectors
  • Immunoblotting
  • Insulin-Like Growth Factor I / pharmacology*
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects*
  • Patch-Clamp Techniques
  • Phosphorus Radioisotopes
  • Phosphotyrosine / biosynthesis
  • Phosphotyrosine / genetics
  • Phosphotyrosine / physiology*
  • Precipitin Tests
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Rats
  • Stimulation, Chemical
  • Tyrosine / genetics
  • Tyrosine / physiology*
  • src-Family Kinases / metabolism


  • Calcium Channel Agonists
  • Calcium Channels, L-Type
  • Nerve Tissue Proteins
  • Phosphorus Radioisotopes
  • Phosphotyrosine
  • Tyrosine
  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins pp60(c-src)
  • src-Family Kinases