Potentiation of neuronal L calcium channels by IGF-1 requires phosphorylation of the alpha1 subunit on a specific tyrosine residue.
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.
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
K K
KK
Bence-Hanulec
J
J
Marshall
L A
LA
Blair
D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002384:Catalysis; D002460:Cell Line; D005822:Genetic Vectors; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010761:Phosphorus Radioisotopes; D019000:Phosphotyrosine / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011233:Precipitin Tests; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D013268:Stimulation, Chemical; D014443:Tyrosine / Q000235:genetics / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D009419:Nerve Tissue Proteins; D010761:Phosphorus Radioisotopes; D019000:Phosphotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases