Journal article
Molecular mechanism of convergent regulation of brain Na(+) channels by protein kinase C and protein kinase A anchored to AKAP-15
Molecular and cellular neuroscience, v 21(1), pp 63-80
01 Sep 2002
PMID: 12359152
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Activation of D1-like dopamine (DA) receptors reduces peak Na(+) current in hippocampal neurons voltage-dependent in a manner via phosphorylation of the alpha subunit. This modulation is dependent upon activation of cAMP-dependent protein kinase (PKA) and requires phosphorylation of serine 573 (S573) in the intracellular loop connecting homologous domains I and II (L(I-II)) by PKA anchored to A kinase anchoring protein-15 (AKAP-15). Activation of protein kinase C (PKC) also reduces peak Na(+) currents and enhances the strength of the PKA modulatory pathway. Here we probe the molecular mechanism responsible for the convergent effects of PKA and PKC on brain Na(v)1.2a channels. Analysis of the interaction of AKAP-15 with the intracellular loops of the Na(v)1.2a channel shows that it binds to L(I-II), thereby targeting PKA directly to its sites of phosphorylation on the Na(+) channel by specific protein-protein interactions. Mutagenesis and expression experiments indicate that reduction of peak Na(+) current by PKC requires S554 and S573 in L(I-II) in addition to S1506 in the inactivation gate. In addition, PKC-dependent phosphorylation of S576 in L(I-II) is necessary for enhancement of PKA modulation of brain Na(+) channels. When S576 is phosphorylated by PKC, the increase in modulation by PKA activation requires phosphorylation of S687 in L(I-II). Thus, the maximal modulation of these Na(+) channels by concurrent activation of PKA and PKC requires phosphorylation at four distinct sites in L(I-II): S554, S573, S576, and S687. This convergent regulation provides a novel mechanism by which information from multiple signaling pathways may be integrated at the cellular level in the hippocampus and throughout the central nervous system.
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Details
- Title
- Molecular mechanism of convergent regulation of brain Na(+) channels by protein kinase C and protein kinase A anchored to AKAP-15
- Creators
- Angela R Cantrell - University of WashingtonVictoria C Tibbs - University of WashingtonFrank H Yu - University of WashingtonBrian J Murphy - University of WashingtonElizabeth M Sharp - University of WashingtonYusheng Qu - University of WashingtonWilliam A Catterall - University of WashingtonTodd Scheuer - University of Washington
- Publication Details
- Molecular and cellular neuroscience, v 21(1), pp 63-80
- Grant note
- NS15751 / NINDS NIH HHS MH01669 / NIMH NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000178200000006
- Scopus ID
- 2-s2.0-0036395114
- Other Identifier
- 991021902530304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences