Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PICK1 protein interacts in neurons with the AMPA-type glutamate receptor subunit 2 (GluR2) and with several other membrane receptors via its single PDZ domain. We show that PICK1 also binds in neurons and in heterologous cells to protein kinase Calpha (PKCalpha) and that the interaction is highly dependent on the activation of the kinase. The formation of PICK1-PKCalpha complexes is strongly induced by TPA, and PICK1-PKCalpha complexes are cotargeted with PICK1-GluR2 complexes to spines, where GluR2 is found to be phosphorylated by PKC on serine 880. PICK1 also reduces the plasma membrane levels of the GluR2 subunit, consistent with a targeting function of PICK1 and a PKC-facilitated release of GluR2 from the synaptic anchoring proteins ABP and GRIP. This work indicates that PICK1 functions as a targeting and transport protein that directs the activated form of PKCalpha to GluR2 in spines, leading to the activity-dependent release of GluR2 from synaptic anchor proteins and the PICK1-dependent transport of GluR2 from the synaptic membrane.
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PMID:PICK1 targets activated protein kinase Calpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. 1146 13

ASIC3, an acid-sensing ion channel subunit expressed essentially in sensory neurons, has been proposed to be involved in pain. We show here for the first time that native ASIC3-like currents were increased in cultured dorsal root ganglion (DRG) neurons following protein kinase C (PKC) stimulation. This increase was induced by the phorbol ester PDBu and by pain mediators, such as serotonin, which are known to activate the PKC pathway through their binding to G protein-coupled receptors. We demonstrate that this regulation involves the silent ASIC2b subunit, an ASIC subunit also expressed in sensory neurons. Indeed, heteromultimeric ASIC3/ASIC2b channels, but not homomeric ASIC3 channels, are positively regulated by PKC. The increase of ASIC3/ASIC2b current is accompanied by a shift in its pH dependence toward more physiological pH values and may lead to an increase of sensory neuron excitability. This regulation by PKC requires PICK-1 (protein interacting with C kinase), a PDZ domain-containing protein, which interacts with the ASIC2b C terminus.
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PMID:ASIC2b-dependent regulation of ASIC3, an essential acid-sensing ion channel subunit in sensory neurons via the partner protein PICK-1. 1497 85

In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase-mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation and immunofluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell.
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PMID:Kinase signaling cascades in the mitochondrion: a matter of life or death. 1558 66

The metabotropic glutamate receptor 7 (mGluR7) is widely expressed throughout the brain and primarily localized at presynaptic active zones, where it is thought to regulate neurotransmitter release. Protein interacting with C kinase 1 (PICK1), a postsynaptic density protein-95/disc-large tumor suppressor protein/zonula occludens-1 (PDZ)-domain protein, binds to the three C-terminal amino acids (-LVI) of the predominant mGluR7 splice variant, mGluR7a, and has been implicated in the synaptic clustering of this receptor. Here, we generated knock-in mice in which the C-terminal LVI coding sequence of exon 10 of the mGluR7 gene was replaced by three alanine codons (-AAA). Immunoprecipitation showed that the PICK1-mGluR7a interaction is disrupted in mGluR7a(AAA/AAA) mice. However, the synaptic localization of mGluR7a was not altered in cultured hippocampal neurons and brain sections prepared from the knock-in animals. In cerebellar granule cell cultures, the group III mGluR agonist l-AP-4 decreased the frequency of spontaneous excitatory currents in neurons derived from wild-type but not mGluR7a(AAA/AAA) mice, consistent with the interaction between mGluR7a and PICK1 being required for protein kinase C-mediated inhibition of glutamate release. At the behavioral level, the mGluR7a(AAA/AAA) mice showed no deficits in motor coordination, pain sensitivity, and anxiety but exhibited significant defects in hippocampus-dependent spatial working memory. In addition, they displayed a high susceptibility to the convulsant drug pentylenetetrazole. Together, these results indicate that PICK1 binding to the C-terminal region of mGluR7a is crucial for agonist-triggered presynaptic signaling in vivo.
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PMID:Knock-in mice lacking the PDZ-ligand motif of mGluR7a show impaired PKC-dependent autoinhibition of glutamate release, spatial working memory deficits, and increased susceptibility to pentylenetetrazol. 1871 19

There are two major forms of long-term depression (LTD) of synaptic transmission in the central nervous system that require activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). In synapses in the perirhinal cortex, we have directly compared the Ca(2+) signaling mechanisms involved in NMDAR-LTD and mGluR-LTD. While both forms of LTD involve Ca(2+) release from intracellular stores, the Ca(2+) sensors involved are different; NMDAR-LTD involves calmodulin, while mGluR-LTD involves the neuronal Ca(2+) sensor (NCS) protein NCS-1. In addition, there is a specific requirement for IP3 and PKC, as well as protein interacting with C kinase (PICK-1) in mGluR-LTD. NCS-1 binds directly to PICK1 via its BAR domain in a Ca(2+)-dependent manner. Furthermore, the NCS-1-PICK1 association is stimulated by activation of mGluRs, but not NMDARs, and introduction of a PICK1 BAR domain fusion protein specifically blocks mGluR-LTD. Thus, NCS-1 plays a distinct role in mGluR-LTD.
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PMID:Metabotropic glutamate receptor-mediated LTD involves two interacting Ca(2+) sensors, NCS-1 and PICK1. 1910 14

Constitutive and activity-dependent regulation of the AMPA receptor GluR2 content is recognized as an important mediator of both neuronal plasticity and vulnerability to excitotoxic neuron death. In the latter case, inclusion of GluR2 protects against glutamate excitotoxicity in CNS disease by lowering receptor single-channel conductance and preventing deleterious calcium influx. We investigated the hypothesis that aberrations in GluR2 trafficking after in vitro and in vivo cerebral trauma contribute to excitotoxicity and associated calcium-dependent cell death processes. First, in an in vitro model of traumatic brain injury (TBI), we observed PICK1 and N-methyl-D-aspartic acid (NMDA) receptor-dependent phosphorylation and internalization of GluR2. The contributing cell signaling mechanisms involved enhanced binding between PKCalpha (the kinase that phosphorylates GluR2) and PICK1 (its PDZ-binding partner), and a novel protein interaction between PKCalpha and the NMDA receptor scaffolding protein PSD-95. Functionally, these phenomena enhanced single cell AMPAR mEPSCs and protracted calcium extrusion. In vivo TBI similarly promoted GluR2 phosphorylation and internalization, with enhanced expression of calcium-permeable AMPARs in the injured hippocampus. Peptide-mediated perturbation of the PKCalpha/PICK1 protein interaction after trauma preserved surface GluR2 expression, attenuated AMPAR-mediated toxicity, and occluded the sensitivity of neuronal physiology to calcium-permeable AMPAR antagonists. These findings suggest that experimental TBI promotes the expression of injurious GluR2-lacking AMPARs, thereby enhancing cellular vulnerability to secondary excitotoxicity.
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PMID:PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma. 1964 8