Insulin-like growth factor-1 modulation of CaV1.3 calcium channels depends on Ca2+ release from IP3-sensitive stores and calcium/calmodulin kinase II phosphorylation of the alpha1 subunit EF hand.
In neurons, L-type calcium channels (CaV1.2 and CaV1.3) regulate an extensive range of functions. However, the roles of CaV1.3-containing L channels, which are physiologically and pharmacologically distinct from the better understood CaV1.2 channels, are only beginning to be determined. We find that CaV1.3 channels are modulated by the insulin-like growth factor-1/receptor tyrosine kinase (IGF-1/RTK) through a signaling pathway that involves phospholipase C, calcium release from IP3-sensitive internal stores, and calcium/calmodulin kinase II. In addition, we find that the IGF-1-induced modulation requires phosphorylation of a specific serine residue, S1486, in the EF hand motif of the CaV1.3 subunit. This modulation alters CaV1.3 activity, causing a left shift in the current-voltage relationship and strongly potentiating peak currents at hyperpolarized membrane potentials. We also find that CaV1.3 channels and their RTK-dependent potentiation contribute to the regulation of the survival-promoting transcription factor cAMP response element-binding protein (CREB): in both cortical and hippocampal neurons, depolarization and IGF-1 rapidly increase phospho-CREB levels in a manner that requires CaV1.3 activity and the S1486 phosphorylation site to achieve a full effect. Although the full effects of CaV1.3 channels remain to be determined, their preferential localization to dendritic shafts and spine heads coupled with their ability to activate at relatively hyperpolarized and even subthreshold potentials suggests that CaV1.3 activity may subserve different cellular functions from CaV1.2 and, in particular, may be important in transducing signals initiated by excitatory neurotransmission.
Gao
Lei
L
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
Blair
Leslie A C
LA
Salinas
Gregory D
GD
Needleman
Leigh A
LA
Marshall
John
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004357:Drug Synergism; D020832:EF Hand Motifs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D007295:Inositol Phosphates; D007527:Isoenzymes; C419385:L-type calcium channel alpha(1C); D007334:Insulin-Like Growth Factor I; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D002118:Calcium