Abstract
Ca2+ influx controls multiple neuronal functions including neurotransmitter release, protein phosphorylation, gene expression, and synaptic plasticity. Brain L-type Ca2+ channels, which contain either α(1C) or α(1D) as their pore-forming subunits, are an important source of calcium entry into neurons. α(1C) exists in long and short forms, which are differentially phosphorylated, and C-terminal truncation of α(1C) increases its activity ≃4-fold in heterologous expression systems. Although most L- type calcium channels in brain are localized in the cell body and proximal dendrites, α(1C) subunits in the hippocampus are also present in clusters along the dendrites of neurons. Examination by electron microscopy shows that these clusters of α(1C) are localized in the postsynaptic membrane of excitatory synapses, which are known to contain glutamate receptors. Activation of N-methyl-D-aspartate (NMDA)-specific glutamate receptors induced the conversion of the long form of α(1C) into the short form by proteolytic removal of the C terminus. Other classes of Ca2+ channel α1 subunits were unaffected. This proteolytic processing reaction required extracellular calcium and was blocked by inhibitors of the calcium-activated protease calpain, indicating that calcium entry through NMDA receptors activated proteolysis of α(1C) by calpain. Purified calpain catalyzed conversion of the long form of immunopurified α(1C) to the short form in vitro, consistent with the hypothesis that calpain is responsible for processing of α(1C) in hippocampal neurons. Our results suggest that NMDA receptor-induced processing of the postsynaptic class C L-type Ca2+ channel may persistently increase Ca2+ influx following intense synaptic activity and may influence Ca2+-dependent processes such as protein phosphorylation, synaptic plasticity, and gene expression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3362-3367 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 93 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 16 1996 |
| Externally published | Yes |
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- General
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N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons. / Hell, Johannes W; Westenbroek, Ruth E.; Breeze, Liam J.; Wang, Kevin K W; Chavkin, Charles; Catterall, William A.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 8, 16.04.1996, p. 3362-3367.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons
AU - Hell, Johannes W
AU - Westenbroek, Ruth E.
AU - Breeze, Liam J.
AU - Wang, Kevin K W
AU - Chavkin, Charles
AU - Catterall, William A.
PY - 1996/4/16
Y1 - 1996/4/16
N2 - Ca2+ influx controls multiple neuronal functions including neurotransmitter release, protein phosphorylation, gene expression, and synaptic plasticity. Brain L-type Ca2+ channels, which contain either α(1C) or α(1D) as their pore-forming subunits, are an important source of calcium entry into neurons. α(1C) exists in long and short forms, which are differentially phosphorylated, and C-terminal truncation of α(1C) increases its activity ≃4-fold in heterologous expression systems. Although most L- type calcium channels in brain are localized in the cell body and proximal dendrites, α(1C) subunits in the hippocampus are also present in clusters along the dendrites of neurons. Examination by electron microscopy shows that these clusters of α(1C) are localized in the postsynaptic membrane of excitatory synapses, which are known to contain glutamate receptors. Activation of N-methyl-D-aspartate (NMDA)-specific glutamate receptors induced the conversion of the long form of α(1C) into the short form by proteolytic removal of the C terminus. Other classes of Ca2+ channel α1 subunits were unaffected. This proteolytic processing reaction required extracellular calcium and was blocked by inhibitors of the calcium-activated protease calpain, indicating that calcium entry through NMDA receptors activated proteolysis of α(1C) by calpain. Purified calpain catalyzed conversion of the long form of immunopurified α(1C) to the short form in vitro, consistent with the hypothesis that calpain is responsible for processing of α(1C) in hippocampal neurons. Our results suggest that NMDA receptor-induced processing of the postsynaptic class C L-type Ca2+ channel may persistently increase Ca2+ influx following intense synaptic activity and may influence Ca2+-dependent processes such as protein phosphorylation, synaptic plasticity, and gene expression.
AB - Ca2+ influx controls multiple neuronal functions including neurotransmitter release, protein phosphorylation, gene expression, and synaptic plasticity. Brain L-type Ca2+ channels, which contain either α(1C) or α(1D) as their pore-forming subunits, are an important source of calcium entry into neurons. α(1C) exists in long and short forms, which are differentially phosphorylated, and C-terminal truncation of α(1C) increases its activity ≃4-fold in heterologous expression systems. Although most L- type calcium channels in brain are localized in the cell body and proximal dendrites, α(1C) subunits in the hippocampus are also present in clusters along the dendrites of neurons. Examination by electron microscopy shows that these clusters of α(1C) are localized in the postsynaptic membrane of excitatory synapses, which are known to contain glutamate receptors. Activation of N-methyl-D-aspartate (NMDA)-specific glutamate receptors induced the conversion of the long form of α(1C) into the short form by proteolytic removal of the C terminus. Other classes of Ca2+ channel α1 subunits were unaffected. This proteolytic processing reaction required extracellular calcium and was blocked by inhibitors of the calcium-activated protease calpain, indicating that calcium entry through NMDA receptors activated proteolysis of α(1C) by calpain. Purified calpain catalyzed conversion of the long form of immunopurified α(1C) to the short form in vitro, consistent with the hypothesis that calpain is responsible for processing of α(1C) in hippocampal neurons. Our results suggest that NMDA receptor-induced processing of the postsynaptic class C L-type Ca2+ channel may persistently increase Ca2+ influx following intense synaptic activity and may influence Ca2+-dependent processes such as protein phosphorylation, synaptic plasticity, and gene expression.
UR - http://www.scopus.com/inward/record.url?scp=0029915158&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029915158&partnerID=8YFLogxK
U2 - 10.1073/pnas.93.8.3362
DO - 10.1073/pnas.93.8.3362
M3 - Article
C2 - 8622942
AN - SCOPUS:0029915158
VL - 93
SP - 3362
EP - 3367
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -