A PKCε–ENH–channel complex specifically modulates N-type Ca2+ channels

Abstract

Multiple protein kinase C (PKC) isozymes are present in neurons, where they regulate a variety of cellular functions. Due to the lack of specific PKC isozyme inhibitors, it remains unknown how PKC acts on its selective target(s) and achieves its specific actions. Here we show that a PKC binding protein, enigma homolog (ENH), interacts specifically with both PKCepsilon and N-type Ca2+ channels, forming a PKCepsilon-ENH-Ca2+ channel macromolecular complex. Coexpression of ENH facilitated modulation of N-type Ca2+ channel activity by PKC. Disruption of the complex reduced the potentiation of the channel activity by PKC in neurons. Thus, ENH, by interacting specifically with both PKCepsilon and the N-type Ca2+ channel, targets a specific PKC to its substrate to form a functional signaling complex, which is the molecular mechanism for the specificity and efficiency of PKC signaling.

Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders

“…38 Considering that PKC activity is altered in bipolar disorder, and antibipolar drugs such as lithium and valproate regulate the PKC signaling cascade, 3,18 upregulation of LIM may be involved in the pathophysiology of bipolar disorder, and may also be related to the common pathophysiology of major mental disorders.…”

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

“…The role of ENH has been mostly studied in cardiac and skeletal muscle cells, where ENH has been proposed as a key factor for the integrity of the actin cytoskeleton in differentiated myocytes (19). However, recent reports show that ENH binds to the N-type calcium channel and suggest that a PKC-ENH-calcium channel complex regulates channel activity in neurons (22). Our isolation of ENH from a fetal brain cDNA library suggests that this protein may be implicated in neural development as well.…”

A Protein Phosphatase 2cα-Ca2+Channel Complex for Dephosphorylation of Neuronal Ca2+Channels Phosphorylated by Protein Kinase C

“…Details of screening have been published previously (Chen et al, 2003;Maeno-Hikichi et al, 2003). The C terminus of ␣ 1A (CaV2.1, amino acid residues 1819 -2422; GenBank accession number X57477), ␣ 1B (CaV2.2, 1707-2339; GenBank accession number M94172), or ␣ 1C (CaV1.2, 1505-2171; GenBank accession number X15539) subunit was used as bait to screen a rat brain cDNA library (OriGene, Rockville, MD).…”

“…Pulldown assays were performed as described previously (Chen et al, 2003;Maeno-Hikichi et al, 2003). Briefly, 35 S-labeled proteins were synthesized using an in vitro protein translation kit (Promega, Madison, WI).…”