Affinage

PRKCG

Protein kinase C gamma type · UniProt P05129

Length
697 aa
Mass
78.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PKCγ (PRKCG) is a calcium- and diacylglycerol-dependent serine/threonine kinase that functions as a critical signaling node in neuronal circuit development, synaptic plasticity, pain processing, and diverse non-neuronal signaling pathways. In cerebellar Purkinje cells, PKCγ phosphorylates CRMP2 at Thr555 to regulate dendritic outgrowth, controls climbing fiber synapse pruning and long-term depression (LTD), and is negatively regulated by DGKγ-mediated DAG consumption, 14-3-3ε binding to its C1B domain, and AMPK α1-mediated inhibition (PMID:32860158, PMID:32033984, PMID:15459208, PMID:31936169). In the spinal dorsal horn, PKCγ-expressing interneurons receive myelinated low-threshold mechanoreceptor input and gate tactile signals into nociceptive circuits; PKCγ-null mice lack neuropathic pain and fail to sustain NMDA-dependent hyperexcitability after tissue injury (PMID:9323205, PMID:18685019, PMID:11438608). Missense mutations in the C1 domain of PRKCG cause spinocerebellar ataxia type 14 (SCA14), in which PKCγ undergoes misfolding, amyloid-like aggregation, and combined gain- and loss-of-function that drives Purkinje cell degeneration (PMID:25217572, PMID:30249303, PMID:21976518).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    The question of whether PKCγ is required for pain sensation was resolved: PKCγ-null mice retained normal acute nociception but completely failed to develop neuropathic pain, establishing PKCγ as selectively required for injury-induced pain sensitization rather than baseline pain processing.

    Evidence PKCγ knockout mouse with behavioral pain testing across multiple paradigms

    PMID:9323205

    Open questions at the time
    • Downstream substrates mediating the pain-gating function were unknown
    • The circuit position of PKCγ interneurons relative to afferent types was not determined
    • Mechanism of transition from acute to persistent hyperexcitability was unclear
  2. 2001 High

    PKCγ was shown to mediate the transition from short-lived to persistent spinal hyperexcitability via NMDA-dependent circuits, explaining why neuropathic pain requires PKCγ while acute pain does not.

    Evidence Electrophysiology of wide dynamic range neurons in PKCγ-null versus wild-type mice with NMDA antagonist epistasis

    PMID:11438608

    Open questions at the time
    • Identity of the afferent inputs activating PKCγ interneurons was unresolved
    • Direct phosphorylation substrates in the spinal pain circuit were unknown
  3. 2002 High

    PKCγ was demonstrated to function outside the nervous system as a direct kinase for syndecan-2, establishing asymmetric phosphorylation as a mechanism for left-right axis determination during Xenopus gastrulation.

    Evidence In vivo phosphorylation assays with dominant-negative and constitutively active PKCγ constructs in Xenopus ectodermal cells

    PMID:12507425

    Open questions at the time
    • Whether this developmental role is conserved in mammals was not tested
    • The upstream signal generating asymmetric PKCγ activation was not identified
  4. 2003 High

    PKCγ was identified as the kinase responsible for connexin phosphorylation and gap junction regulation in lens cells, revealing a DAG-dependent (calcium-independent) activation mode downstream of IGF-I signaling.

    Evidence Co-immunoprecipitation, in vitro kinase assay, and scrape-loading dye-transfer in lens epithelial cells

    PMID:12601045

    Open questions at the time
    • Specific phosphorylation sites on Cx43 were not mapped
    • Whether other connexins (Cx50, Cx46) were similarly regulated was not yet tested
  5. 2004 High

    14-3-3ε was established as an endogenous inhibitor that sequesters PKCγ via its C1B domain, and competitive release of PKCγ from 14-3-3ε was shown to trigger membrane translocation, Cx43 phosphorylation, and gap junction closure, revealing a discrete regulatory mechanism controlling PKCγ activation state.

    Evidence Synthetic peptide competition binding assays, co-IP, MALDI-TOF MS for binding sites, and functional gap junction assays

    PMID:15459208

    Open questions at the time
    • In vivo relevance of 14-3-3ε regulation of PKCγ was not demonstrated
    • Whether 14-3-3ε regulates PKCγ in neurons was unknown
  6. 2005 High

    The first SCA14 mutations in PKCγ were functionally characterized: the H101Q mutation reduced PKCγ protein stability and the S119P mutation caused aggregation in Purkinje cells with dominant-negative effects on wild-type PKCγ, LTD blockade, and impaired climbing fiber synapse pruning, linking PKCγ misfolding to cerebellar degeneration.

    Evidence HEK293 transfection (H101Q), lentiviral expression in mouse Purkinje cells in vivo (S119P) with electrophysiology and morphological analysis

    PMID:16189624 PMID:21976518

    Open questions at the time
    • Whether aggregation or loss of kinase function was the primary pathogenic driver was unresolved
    • In vitro reconstitution of aggregation had not been achieved
  7. 2007 Medium

    A spinal circuit mechanism was elucidated: disinhibition (loss of glycinergic tone) activates PKCγ interneurons to gate touch into the nociceptive pathway via NMDA receptor-dependent signaling, establishing PKCγ as the molecular switch for mechanical allodynia.

    Evidence In vivo electrophysiology with strychnine disinhibition, pharmacological PKCγ inhibition, and NMDA antagonism

    PMID:17987109

    Open questions at the time
    • The specific afferent fiber type driving PKCγ interneurons was not yet anatomically defined
    • Downstream targets of PKCγ in this circuit were not identified
  8. 2008 High

    The afferent input to PKCγ interneurons was anatomically resolved: VGLUT1-positive myelinated low-threshold mechanoreceptors (not unmyelinated nociceptors) synapse directly onto PKCγ interneurons, explaining how touch signals access pain circuits after disinhibition. Separately, PKCγ was recruited to the mu-opioid receptor via HINT1/zinc-dependent scaffolding to phosphorylate MOR and attenuate opioid signaling.

    Evidence Electron microscopic double labeling and VGLUT1 immunohistochemistry (afferent identity); co-IP with HINT1 knockdown and zinc chelation (MOR pathway)

    PMID:18652891 PMID:18685019

    Open questions at the time
    • Whether PKCγ phosphorylation of MOR is direct was not shown by in vitro kinase assay
    • The full circuit downstream of PKCγ interneurons to projection neurons was not mapped
  9. 2010 High

    PKCγ was positioned within the Src→PLD1→PKCγ→cPLA2 signaling axis driving VEGF-induced retinal angiogenesis, demonstrating a non-neuronal role in endothelial cell migration, proliferation, and neovascularization, while SCA14 mutant PKCγ was shown to be selectively cleared by autophagy.

    Evidence Multiple inhibition strategies (siRNA, dominant-negative, pharmacological) with in vitro and in vivo retinal models; Atg5-KO fibroblasts for autophagy dependence

    PMID:20398063 PMID:20421451 PMID:21536681

    Open questions at the time
    • Direct PKCγ phosphorylation of cPLA2 was not demonstrated by in vitro kinase assay
    • Whether autophagy clearance of mutant PKCγ is sufficient to prevent neurodegeneration in vivo was untested
  10. 2013 High

    FRET-FLIM revealed that SCA14 C1B domain mutations cause partial unfolding of PKCγ with an exposed C-terminus, accelerated membrane translocation, and accumulation of fully phosphorylated protein in the insoluble fraction, providing a structural basis for how point mutations drive both hyperactivation and aggregation.

    Evidence FRET-fluorescence lifetime imaging in living cells with PDK1 co-expression rescue of insolubilization

    PMID:24134140

    Open questions at the time
    • High-resolution structural data for the misfolded state was lacking
    • Whether PDK1 rescue is therapeutically exploitable was unknown
  11. 2014 High

    PKCγ was identified as a direct kinase for βPIX at Ser583, linking PKCγ to Ca²⁺-evoked dopamine release in the striatum; PKCγ-null mice develop parkinsonian syndrome, broadening PKCγ's neurological roles beyond pain and cerebellar function. PKCγ amyloid-like fibril formation was reconstituted in vitro from the C1A and kinase domains, with SCA14 mutations accelerating fibrillization.

    Evidence In vitro kinase assay with phospho-site mutagenesis and rescue in PKCγ-KO mice; cell-free fibril formation assay with domain deletion mapping

    PMID:25009260 PMID:25217572

    Open questions at the time
    • Whether βPIX phosphorylation is the sole mechanism for dopamine release regulation was not tested
    • The amyloid fibril structure was not resolved at atomic level
  12. 2016 High

    A sequential kinase cascade (Hck→PKCδ→PKCγ) was defined for lysoPC-mediated neutrophil priming, with PKCγ phosphorylating p47phox to enable NADPH oxidase activation, establishing PKCγ as an effector in innate immune priming.

    Evidence FRET-confirmed PKCδ–PKCγ interaction, phospho-site identification, PKCγ-KO PMNs, in vivo TRALI model

    PMID:27531930

    Open questions at the time
    • Whether PKCγ directly phosphorylates p47phox was not shown by in vitro kinase assay
    • Relevance to human neutrophil biology was not confirmed
  13. 2018 High

    Analysis of patient-derived iPSCs and post-mortem SCA14 cerebellum confirmed that C1 domain mutations cause both gain-of-function (hyperphosphorylation of substrates) and loss-of-function (aggregation/mislocalization) in human tissue, while Hsp70 was identified as a chaperone that binds PKCγ's kinase and C2 domains and can be pharmacologically upregulated to attenuate aggregation and apoptosis.

    Evidence Patient iPSCs, post-mortem immunohistochemistry, substrate phosphorylation assays; co-IP domain mapping, celastrol/herbimycin A rescue in primary Purkinje cells

    PMID:30093405 PMID:30249303

    Open questions at the time
    • Whether Hsp70 upregulation is neuroprotective in vivo in SCA14 models was not shown
    • The relative contribution of gain- versus loss-of-function to disease progression remained unquantified
  14. 2020 High

    DGKγ was established as a direct negative regulator of PKCγ in Purkinje cells by metabolizing DAG to phosphatidic acid; DGKγ-KO mice phenocopy PKCγ hyperactivation with impaired LTD and dendritic retraction, rescued by PKCγ-specific inhibition. CRMP2 was identified by IP-MS as a direct PKCγ substrate phosphorylated at Thr555 to regulate Purkinje cell dendritic outgrowth, confirmed by a T555A knock-in mouse.

    Evidence Conditional DGKγ KO with pharmacological rescue; IP-MS substrate identification, proximity ligation, phospho-site mutagenesis, T555A knock-in mouse

    PMID:32033984 PMID:32860158

    Open questions at the time
    • Additional PKCγ substrates in Purkinje cells likely remain unidentified
    • How CRMP2 phosphorylation interacts with other PKCγ-dependent dendritic signals was not tested
  15. 2021 High

    A pseudosubstrate domain knock-in (A24E) proved that constitutive PKCγ kinase activation paradoxically leads to protein degradation and reduced steady-state levels while still driving aberrant Purkinje cell morphology and ataxia, clarifying that even transient hyperactivation is pathogenic.

    Evidence A24E knock-in mouse with PKC activity measurement, dendritic morphology, and behavioral analysis

    PMID:33478986

    Open questions at the time
    • The degradation pathway (proteasomal vs. autophagic) for constitutively active PKCγ was not defined
    • Whether pharmacological dampening of PKCγ activity could rescue the A24E phenotype was not tested
  16. 2024 High

    TRPM2 was identified as a direct PKCγ-interacting partner via the C2 domain–M2PBM interface, establishing a feedforward loop: TRPM2-mediated Ca²⁺ influx activates PKCγ, which then potentiates extrasynaptic NMDAR activity to amplify excitotoxicity. An interfering peptide disrupting this interaction was neuroprotective in ischemic stroke models.

    Evidence Interaction motif mapping, co-IP, TAT-M2PBM interfering peptide, extrasynaptic NMDAR electrophysiology, ischemic stroke models in vivo

    PMID:38308841

    Open questions at the time
    • Whether PKCγ directly phosphorylates TRPM2 or NMDARs was not determined
    • Long-term efficacy and specificity of TAT-M2PBM in vivo were not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full repertoire of PKCγ substrates in spinal dorsal horn pain circuits, the atomic-resolution structure of PKCγ and its SCA14 aggregates, the relative therapeutic value of targeting gain-of-function versus loss-of-function mechanisms in SCA14, and how PKCγ signaling is coordinated across its diverse neuronal and non-neuronal contexts.
  • No substrate identified in spinal PKCγ interneurons
  • No high-resolution structure of full-length PKCγ or its amyloid fibrils
  • No clinical trial data for PKCγ-targeted therapies in SCA14 or neuropathic pain

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-112316 Neuronal System 6 R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 3
Partners
ARHGEF7DGKGDPYSL2GJA1HINT1HSPA1ATRPM2YWHAE

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PKCγ-null mice display normal acute pain responses but fail to develop neuropathic pain after partial sciatic nerve section, establishing PKCγ as required for injury-induced persistent pain sensitization. PKCγ was found restricted to a small subset of dorsal horn interneurons. PKCγ knockout mouse model, behavioral pain testing, neurochemical analysis Science High 9323205
2001 PKCγ mediates the transition from short-term to long-term hyperexcitability of lamina V nociresponsive neurons after tissue injury (mustard oil). Wild-type mice showed progressive enhancement of wide dynamic range neuron responses while PKCγ-null mice showed hyperexcitability lasting <30 min. PKCγ contributes to a subset of NMDA-dependent spinal circuits underlying persistent pain. Electrophysiological recordings and behavioral assays in PKCγ-null vs wild-type mice, NMDA receptor antagonist pharmacology The Journal of Neuroscience High 11438608
2002 PKCγ mediates phosphorylation of the cytoplasmic domain of syndecan-2 in right (but not left) ectodermal cells during Xenopus gastrulation, and this asymmetric phosphorylation is required for left-right development via syndecan-2-mediated inside-out signaling to adjacent migrating mesodermal cells. In vivo phosphorylation assays, dominant-negative/constitutively active PKCγ constructs, animal cap ectodermal cell experiments in Xenopus Cell High 12507425
2003 IGF-I activates and translocates PKCγ in lens epithelial cells, leading to coimmunoprecipitation with and phosphorylation of connexin 43 (Cx43), resulting in decreased gap junction activity. IGF-I increases endogenous DAG which triggers PKCγ translocation; calcium mobilization is not essential for this effect. Western blot, co-immunoprecipitation, PKC translocation assay, in vitro PKC phosphorylation assay, scrape-loading/dye-transfer gap junction assay, confocal microscopy Investigative Ophthalmology & Visual Science High 12601045
2004 14-3-3ε binds the C1B domain of PKCγ at two sites (C1B1: residues 101-112 and C1B5: residues 141-151) to inhibit PKCγ activity. Synthetic peptides corresponding to these sites compete for 14-3-3ε binding, releasing PKCγ, causing its phosphorylation and membrane translocation, which leads to Cx43 phosphorylation and inhibition of gap junction activity. In vitro and in vivo competition binding assays with synthetic peptides, co-immunoprecipitation, PKC enzyme activity assay, gap junction dye-transfer assay, HPLC, MALDI-TOF MS The Journal of Biological Chemistry High 15459208
2005 Activation of PKCγ by phorbol ester (TPA) in rat lens disassembles Cx50 gap junction channels: PKCγ translocates to membrane fractions containing Cx46, Cx50, and caveolin-1, phosphorylates Cx50 at serines and threonines, and Cx46 only at threonines, leading to decreased Cx50 channel density in gap junctions and increased Cx50 hemichannels in plasma membrane. Freeze-fracture immunolabeling (FRIL), dye-transfer assay, PKCγ activity assay, connexin phosphorylation, co-immunoprecipitation Investigative Ophthalmology & Visual Science High 16123426
2005 The SCA14 H101Q mutation in PRKCG causes decreased PKCγ protein levels in HEK293 cells over time (affecting stability/solubility), leading to reduced PKCγ-dependent phosphorylation and slowly progressive cerebellar ataxia. Transfection of HEK293 cells with normal or mutant construct, time-dependent protein level measurements by Western blot Journal of Human Genetics Medium 16189624
2008 PKCγ interneurons of the spinal dorsal horn are activated by myelinated afferents (VGLUT1-expressing) that respond to innocuous stimuli, not by unmyelinated nociceptors. VGLUT1 synapses were shown pre-synaptic to PKCγ interneurons by electron microscopy, and walking on a rotarod induced Fos in PKCγ interneurons. Transganglionic tracer studies (cholera toxin B, wheat germ agglutinin), transneuronal tracer, light and electron microscopic double labeling, VGLUT1 immunohistochemistry, Fos induction assay The Journal of Neuroscience High 18685019
2008 NMDAR/nNOS cascade activated by morphine provides free zinc ions that recruit inactive PKCγ (via its C1/CRD domain) to the HINT1/RGSZ complex at the C-terminus of the mu-opioid receptor (MOR). DAG then activates this PKCγ to phosphorylate the MOR, reducing its signaling strength. HINT1 knockdown abolishes PKCγ-MOR association and serine phosphorylation of MOR. Intracerebroventricular administration, co-immunoprecipitation, antisense knockdown of HINT1, zinc chelation (TPEN), NMDAR antagonist (MK801), NO donor experiments Cellular Signalling Medium 18652891
2009 Activation of PKCγ by phorbol ester potentiates AMPA receptor-mediated mEPSC amplitude in embryonic zebrafish via NSF- and PICK1-dependent AMPAR trafficking. This process requires DAG, Ca2+, active PKCγ, actin polymerization, SNARE proteins, and GluR2 association with both NSF and PICK1. Whole-cell patch-clamp recordings, pharmacological blockade with blocking peptides (NSF, PICK1, GluR2), actin-polymerization blocker, tetanus toxin PNAS Medium 19366675
2010 VEGF activates PKCγ through a Src-dependent PLD1 pathway in human retinal microvascular endothelial cells. Inhibition of Src, PLD1, or PKCγ via pharmacologic, dominant negative, or siRNA approaches significantly attenuated VEGF-induced endothelial cell migration, proliferation, and tube formation, as well as hypoxia-induced retinal neovascularization. siRNA knockdown, dominant negative mutants, pharmacological inhibitors, endothelial cell migration/proliferation/tube formation assays, in vivo retinal neovascularization model Blood High 20421451
2010 Mutant PKCγ (S119P) associated with SCA14 aggregates in Purkinje cells, impairs climbing fiber synapse pruning, blocks long-term depression (LTD) at parallel fiber synapses, and increases slow EPSC amplitude. Mutant PKCγ colocalizes with and acts in a dominant-negative manner on wild-type PKCγ, and decreases membrane residence time of PKCα after depolarization-induced translocation. Lentiviral expression of mutant PKCγ-GFP in mouse Purkinje cells in vivo, electrophysiology (LTD, EPSCs, CF synapse pruning), immunohistochemistry The Journal of Neuroscience High 21976518
2010 Mutant PKCγ causing SCA14 is selectively degraded by autophagy. Rapamycin (autophagic inducer) accelerated clearance of mutant (but not wild-type) PKCγ aggregates, an effect absent in Atg5-deficient cells that cannot perform autophagy. Adenoviral tetracycline-regulated expression system, rapamycin and lithium treatment, Atg5-knockout fibroblasts as genetic control, aggregate clearance and protein degradation assays Genes to Cells Medium 20398063
2011 PKCγ is required for ethanol-induced increases in GABA(A) receptor α4 subunit expression in cultured cortical neurons. PKCγ siRNA knockdown prevented ethanol-induced α4 upregulation, while PKCβ isoform inhibition had no effect. siRNA knockdown of PKCγ vs PKCβ pseudosubstrate inhibition, P2 fractionation, surface biotinylation, whole-cell patch clamp Journal of Neurochemistry Medium 21155805
2011 NO-released zinc ions recruit both Raf-1 and PKCγ via their cysteine-rich domains (CRDs) simultaneously to HINT1 at the MOR C-terminus. PKCγ enhances Raf-1 function to amplify MEK/ERK1/2 activation at the MOR. Morphine-generated NO mediates this cross-talk between PKC/Src and Raf-1/ERK1/2 pathways implicated in negative control of morphine effects. Co-immunoprecipitation, TPEN zinc chelation, MK801 NMDAR blockade, A-Raf/B-Raf comparison, in vivo intracerebroventricular administration Antioxidants & Redox Signaling Medium 21235400
2011 cPLA2 is an effector downstream of Src-PLD1-PKCγ signaling in VEGF-induced retinal angiogenesis. Inhibition of Src, PLD1, or PKCγ attenuated VEGF-induced cPLA2 phosphorylation and arachidonic acid release, and exogenous arachidonic acid rescued endothelial function from cPLA2 siRNA inhibition. siRNA knockdown, pharmacological inhibition, cPLA2 phosphorylation assay, arachidonic acid release assay, in vivo retinal neovascularization model The Journal of Biological Chemistry Medium 21536681
2012 PKCγ participates in food-mediated circadian entrainment by stabilizing BMAL1 and reducing its ubiquitylation in a deubiquitination-dependent manner. PKCγ-null mice failed to show reduced late-night activity in response to daytime restricted feeding, and PKCγ exhibited food-entrainment-induced activation changes in cerebral cortex. PKCγ knockout mice, behavioral analysis, molecular analysis of clock gene oscillations, BMAL1 stability and ubiquitylation assays PNAS Medium 23185022
2014 PKCγ directly phosphorylates βPIX (Pak-interacting exchange factor-β) at Ser583 and indirectly at Ser340 in cells, and this phosphorylation is required for Ca2+-evoked dopamine release in the striatum. PKCγ-KO mice show parkinsonian syndrome with impaired striatal dopamine release. PKCγ-KO mice, phosphoproteome analysis, in vitro kinase assay (direct phosphorylation), βPIX knockdown with rescue by wild-type vs phospho-site mutants, Ca2+-evoked dopamine release assay in PC12 cells The Journal of Neuroscience High 25009260
2014 EGF activates PLCγ1, which signals through Ca2+ and PKCγ to promote plasma membrane translocation of Hsp90α. PKCγ overexpression increases extracellular vesicle release containing Hsp90α and promotes tumor cell motility and metastasis in vitro and in vivo; a neutralizing antibody against Hsp90α blocks these PKCγ-induced effects. siRNA knockdown, PKCγ overexpression, inhibitor studies, in vitro migration assays, in vivo tumor metastasis model, neutralizing antibody Traffic Medium 24899266
2014 PKCγ was identified as an amyloidogenic protein capable of forming amyloid-like fibrils in vitro without heat or chemical denaturants, via its C1A and kinase domains. SCA14-associated mutations accelerate amyloid-like fibril formation both in cells and in vitro, and long-term imaging shows aggregates of mutant PKCγ are highly toxic to neuronal cells. In vitro incubation without denaturants, overexpression in cultured cells, live cell time-lapse imaging, identification of amyloid-prone domains by domain deletion Human Molecular Genetics High 25217572
2016 LysoPCs activate PKCγ through a sequential Hck→PKCδ→PKCγ cascade: Hck causes Tyr311/Tyr525 phosphorylation and Thr507 phosphorylation of PKCδ; activated PKCδ then causes Tyr514 and Ser phosphorylation of PKCγ; activated PKCγ then causes phosphorylation and membrane translocation of p47phox. PKCγ-KO PMNs failed to show PKCδ-PKCγ FRET interaction or priming by lysoPCs. Immunoprecipitation, FRET (fluorescence resonance energy transfer), immunoblotting, specific kinase inhibitors, PKCγ KO mice, TRALI in vivo model, intracellular PKC isoform depletion Journal of Leukocyte Biology High 27531930
2018 SCA14 mutations in the C1 domain of PKCγ (H36R and H101Q) cause cytoplasmic mislocalization, aggregation, and hyper-activation of PKCγ (increased substrate phosphorylation). PKCγ aggregates are not efficiently targeted for degradation. Both loss-of-function and gain-of-function mechanisms contribute to SCA14 pathogenesis. Patient-derived iPSCs, post-mortem SCA14 cerebellum, immunohistochemistry, substrate phosphorylation assays, protein localization studies Acta Neuropathologica Communications High 30249303
2018 Endogenous Hsp70 is incorporated into SCA14-associated PKCγ aggregates. PKCγ binds Hsp70 via its kinase domain and C2 domain, with enhanced interaction in SCA14 mutants. Pharmacological up-regulation of Hsp70 (by Hsp90 inhibitors celastrol/herbimycin A) attenuates mutant PKCγ aggregation and apoptosis in Purkinje cells. Co-immunoprecipitation, domain mapping, primary cultured Purkinje cells, Hsp90 inhibitor treatment, apoptosis assay, in vivo celastrol administration The Journal of Biological Chemistry Medium 30093405
2019 PKCγ promotes axonal remodeling in the corticospinal tract by phosphorylating GSK3β, which stabilizes cytosolic β-catenin and increases GAP43 expression, facilitating neuronal differentiation, neurite outgrowth, and axonal branching. In vivo rAAV2/9-mediated delivery of constitutively active PKCγ to CST after unilateral TBI promoted midline crossing of corticospinal fibers and sensorimotor recovery. Loss- and gain-of-function in N2a cells and primary cortical neurons, GSK3β phosphorylation assays, β-catenin and GAP43 Western blot, rAAV2/9 in vivo delivery, axonal tracing, behavioral assays Scientific Reports Medium 31745212
2019 ΔNp63α positively regulates miR-320a, which suppresses PKCγ expression. Loss of ΔNp63α elevates PKCγ levels, increasing Rac1 phosphorylation at Ser71 and cell invasion. Silencing PKCγ or inhibiting PKC reversed increased Rac1 phosphorylation and invasion caused by ΔNp63α knockdown. siRNA knockdown, miRNA mimic overexpression, PKC inhibitor (Gö6976), Rac1 silencing, invasion assays Cell Death & Disease Medium 31515469
2020 DGKγ directly interacts with PKCγ, converts diacylglycerol to phosphatidic acid, and thereby negatively regulates PKCγ activity. DGKγ knockout mice show upregulated PKCγ activity in cerebellum, impaired cerebellar LTD, retracted Purkinje cell dendrites, and impaired motor coordination. cPKC inhibitor rescues dendritic retraction; PKCγ-specific inhibitor (scutellarin) rescues LTD. DGKγ KO mice, Purkinje cell-specific DGKγ KO (tm1d), PKCγ activity assays, cerebellar LTD electrophysiology, dendritic morphology analysis, rescue with Gö6976 and scutellarin, FLP-mediated re-expression rescue eNeuro High 32033984
2020 AMPKα1 inhibits PKCγ kinase activity, thereby decreasing phosphorylation and membrane translocation of Hsp90α and suppressing tumor metastasis. Metformin activates AMPKα1 to inhibit PKCγ-mediated Hsp90α secretion. Mass spectrometry, AMPKα1 overexpression/knockdown, PKCγ kinase activity assay, Hsp90α phosphorylation and secretion assays, in vitro migration/invasion, in vivo metastasis model Cells Medium 31936169
2020 PKCγ-mediated phosphorylation of CRMP2 at Thr555 regulates dendritic outgrowth in cerebellar Purkinje cells. Immunoprecipitation-MS identified CRMP2 as a PKCγ(S361G)-interacting protein; Thr555 phosphorylation is increased in PKCγ(S361G) transgenic Purkinje cells. CRMP2 knockdown and Thr555 site mutants reduce dendritic outgrowth; a T555A knock-in mouse shows reduced dendritic development. Immunoprecipitation-coupled mass spectrometry, Duolink proximity ligation assay, cerebellar slice cultures, miRNA knockdown, phospho-site mutagenesis, T555A knock-in mouse Molecular Neurobiology High 32860158
2021 A pseudosubstrate domain knock-in mutation (A24E) in PKCγ causes constitutive activation of the kinase domain while also promoting dephosphorylation and protein degradation, resulting in dramatically reduced PKCγ protein levels but increased PKC activity. Purkinje cells show short thickened dendrites typical of PKC activation, and mice develop marked ataxia. Knock-in mouse model, PKCγ expression measurement by Western blot, PKC activity assay in Purkinje cells, dendritic morphology analysis, behavioral ataxia testing, RNA profiling The Journal of Neuroscience High 33478986
2024 TRPM2 directly associates with PKCγ via the C2 domain of PKCγ binding to the M2PBM motif on TRPM2. TRPM2-mediated Ca2+ influx promotes PKCγ activation, which subsequently enhances TRPM2-induced potentiation of extrasynaptic NMDAR activity, amplifying excitotoxic neuronal death. Disrupting this interaction with a TAT-M2PBM interfering peptide reduces excitotoxicity and ischemic brain injury. Identification of interaction motif, co-immunoprecipitation, interfering peptide (TAT-M2PBM), M2PBM deletion constructs, extrasynaptic NMDAR electrophysiology, ischemic stroke models Cell Reports High 38308841
2013 SCA14 mutation V138E in PKCγ C1B domain causes partial unfolding of the protein with exposed C-terminus (shown by FRET-FLIM), faster phorbol ester-induced membrane translocation, and accumulation of fully phosphorylated PKCγ in the insoluble fraction. Co-expression of PDK1 (which triggers PKCγ autophosphorylation) rescues the PKCγ-V138E insolubilization phenotype. FRET-fluorescence lifetime imaging microscopy (FRET-FLIM) in living cells, phorbol ester-induced translocation assay, phosphorylation state analysis, PDK1 co-expression rescue Journal of Neurochemistry High 24134140
2007 Glycine inhibitory dysfunction activates a local circuit involving PKCγ-expressing interneurons in the superficial dorsal horn to convert touch into pain. Selective inhibition of PKCγ as well as selective blockade of NMDA receptors in the superficial dorsal horn prevented activation of this circuit and allodynia, establishing PKCγ as required for NMDA-receptor-dependent gating of tactile input to nociceptive neurons. In vivo electrophysiology, segmental glycine inhibition removal (strychnine), anatomical circuit tracing, pharmacological PKCγ inhibition, NMDA receptor antagonism PLoS ONE Medium 17987109

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma. Science (New York, N.Y.) 546 9323205
2007 Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PloS one 150 17987109
2008 Innocuous, not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers. The Journal of neuroscience : the official journal of the Society for Neuroscience 143 18685019
2012 Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ-ERK signaling pathway in the developing brain. Brain research 91 22985497
2000 A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Annals of neurology 90 10939565
2002 PKCgamma regulates syndecan-2 inside-out signaling during xenopus left-right development. Cell 85 12507425
2001 PKCgamma contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 11438608
2005 Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 16319314
2003 Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family. Neurology 77 14694043
2011 Mutant PKCγ in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 67 21976518
2002 Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-gamma expression and decrease of PKA activity. American journal of physiology. Gastrointestinal and liver physiology 56 12505882
2008 NMDAR-nNOS generated zinc recruits PKCgamma to the HINT1-RGS17 complex bound to the C terminus of Mu-opioid receptors. Cellular signalling 53 18652891
2002 Individual differences in spatial memory among aged rats are related to hippocampal PKCgamma immunoreactivity. Hippocampus 53 12000125
2003 IGF-I-induced phosphorylation of connexin 43 by PKCgamma: regulation of gap junctions in rabbit lens epithelial cells. Investigative ophthalmology & visual science 50 12601045
2018 5-HT2A Receptor-Induced Morphological Reorganization of PKCγ-Expressing Interneurons Gates Inflammatory Mechanical Allodynia in Rat. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 30355630
2002 Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2. Cytogenetic and genome research 45 12438709
2018 Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation. Acta neuropathologica communications 42 30249303
2011 PKCγ is required for ethanol-induced increases in GABA(A) receptor α4 subunit expression in cultured cerebral cortical neurons. Journal of neurochemistry 42 21155805
2017 Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCγ/Rac1 pathway in salt-induced hypertension. Scientific reports 39 28338001
2006 Novel PRKCG/SCA14 mutation in a Dutch spinocerebellar ataxia family: expanding the phenotype. Movement disorders : official journal of the Movement Disorder Society 39 16547918
2011 Intrathecal lentiviral-mediated RNA interference targeting PKCγ attenuates chronic constriction injury-induced neuropathic pain in rats. Human gene therapy 36 21087146
2010 PLD1-dependent PKCgamma activation downstream to Src is essential for the development of pathologic retinal neovascularization. Blood 35 20421451
2013 Both Kdr and Flt1 play a vital role in hypoxia-induced Src-PLD1-PKCγ-cPLA(2) activation and retinal neovascularization. Blood 34 23319572
2005 Regulation of lens cell-to-cell communication by activation of PKCgamma and disassembly of Cx50 channels. Investigative ophthalmology & visual science 34 16123426
2011 L-type voltage-dependent calcium channels facilitate acetylation of histone H3 through PKCγ phosphorylation in mice with methamphetamine-induced place preference. Journal of neurochemistry 31 21781114
2012 Exome sequencing in an SCA14 family demonstrates its utility in diagnosing heterogeneous diseases. Neurology 30 22675081
2005 A novel H101Q mutation causes PKCgamma loss in spinocerebellar ataxia type 14. Journal of human genetics 30 16189624
2004 Inhibition of gap junction activity through the release of the C1B domain of protein kinase Cgamma (PKCgamma) from 14-3-3: identification of PKCgamma-binding sites. The Journal of biological chemistry 30 15459208
2011 NO-released zinc supports the simultaneous binding of Raf-1 and PKCγ cysteine-rich domains to HINT1 protein at the mu-opioid receptor. Antioxidants & redox signaling 29 21235400
2003 Alterations in PKCgamma in the mouse hippocampus after prenatal exposure to heroin: a link from cell signaling to behavioral outcome. Brain research. Developmental brain research 29 12524182
2012 PKCγ participates in food entrainment by regulating BMAL1. Proceedings of the National Academy of Sciences of the United States of America 28 23185022
2009 PKCgamma-induced trafficking of AMPA receptors in embryonic zebrafish depends on NSF and PICK1. Proceedings of the National Academy of Sciences of the United States of America 28 19366675
2007 Effects of scutellarin on PKCgamma in PC12 cell injury induced by oxygen and glucose deprivation. Acta pharmacologica Sinica 28 17883942
2006 Identification of a new family of spinocerebellar ataxia type 14 in the Japanese spinocerebellar ataxia population by the screening of PRKCG exon 4. Movement disorders : official journal of the Movement Disorder Society 27 16763984
2015 Subpopulations of PKCγ interneurons within the medullary dorsal horn revealed by electrophysiologic and morphologic approach. Pain 26 25961142
2014 PLCγ1-PKCγ signaling-mediated Hsp90α plasma membrane translocation facilitates tumor metastasis. Traffic (Copenhagen, Denmark) 26 24899266
2011 PKCgamma in Vc and C1/C2 is involved in trigeminal neuropathic pain. Journal of dental research 26 21393551
2005 Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population. Human genetics 26 15841389
2012 Identification of differentially expressed proteins in the spinal cord of neuropathic pain models with PKCgamma silence by proteomic analysis. Brain research 25 22284620
2012 Amitriptyline attenuates astrocyte activation and morphine tolerance in rats: role of the PSD-95/NR1/nNOS/PKCγ signaling pathway. Behavioural brain research 25 22309983
2010 Involvement of the spinal NMDA receptor/PKCγ signaling pathway in the development of bone cancer pain. Brain research 25 20362561
2015 Carbonic Anhydrase 8 Expression in Purkinje Cells Is Controlled by PKCγ Activity and Regulates Purkinje Cell Dendritic Growth. Molecular neurobiology 24 26399641
2013 Transient, 5-HT2B receptor-mediated facilitation in neuropathic pain: Up-regulation of PKCγ and engagement of the NMDA receptor in dorsal horn neurons. Pain 24 23769718
2005 Spatial memory in aged rats is related to PKCgamma-dependent G-protein coupling of the M1 receptor. Neurobiology of aging 24 15585346
2008 Inhibition of PKCgamma membrane translocation mediated morphine preconditioning-induced neuroprotection against oxygen-glucose deprivation in the hippocampus slices of mice. Neuroscience letters 23 18706478
2004 Prenatal heroin exposure alters cholinergic receptor stimulated activation of the PKCbetaII and PKCgamma isoforms. Brain research bulletin 23 15196660
2015 EphrinB-EphB signaling regulates spinal pain processing via PKCγ. Neuroscience 22 26318332
2001 Differential sensitivity to the anxiolytic effects of ethanol and flunitrazepam in PKCgamma null mutant mice. Pharmacology, biochemistry, and behavior 22 11420074
2014 Identification and characterization of PKCγ, a kinase associated with SCA14, as an amyloidogenic protein. Human molecular genetics 21 25217572
2005 Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene. Journal of neurology, neurosurgery, and psychiatry 21 16291902
2021 Protocatechuic acid attenuates isoproterenol-induced cardiac hypertrophy via downregulation of ROCK1-Sp1-PKCγ axis. Scientific reports 20 34462460
2016 Involvement of Spinal CCR5/PKCγ Signaling Pathway in the Maintenance of Cancer-Induced Bone Pain. Neurochemical research 20 27848062
2014 Mechanism of GABA involvement in post-traumatic trigeminal neuropathic pain: activation of neuronal circuitry composed of PKCγ interneurons and pERK1/2 expressing neurons. European journal of pain (London, England) 20 24890317
2011 Activation of cytosolic phospholipase A2 downstream of the Src-phospholipase D1 (PLD1)-protein kinase C γ (PKCγ) signaling axis is required for hypoxia-induced pathological retinal angiogenesis. The Journal of biological chemistry 20 21536681
2010 Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy. Genes to cells : devoted to molecular & cellular mechanisms 20 20398063
1999 Chronic exposure to lead acetate affects the development of protein kinase C activity and the distribution of the PKCgamma isozyme in the rat hippocampus. Neurotoxicology 20 10499359
2013 Protein kinase C gamma (PKCγ) as a novel marker to assess the functional status of the corticospinal tract in experimental autoimmune encephalomyelitis (EAE). Journal of neuroimmunology 19 23385082
2013 PKCγ receptor mediates visceral nociception and hyperalgesia following exposure to PTSD-like stress in the spinal cord of rats. Molecular pain 19 23837410
2020 Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner. Cells 18 31936169
2020 PKCγ interneurons, a gateway to pathological pain in the dorsal horn. Journal of neural transmission (Vienna, Austria : 1996) 18 32108249
2020 DGKγ Knock-Out Mice Show Impairments in Cerebellar Motor Coordination, LTD, and the Dendritic Development of Purkinje Cells through the Activation of PKCγ. eNeuro 17 32033984
2008 Expansion of the phenotypic spectrum of SCA14 caused by the Gly128Asp mutation in PRKCG. Clinical neurology and neurosurgery 17 18986758
2007 PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype. Movement disorders : official journal of the Movement Disorder Society 17 17343273
2021 A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 33478986
2019 ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a. Cell death & disease 16 31515469
2019 Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene. Molecular and cellular neurosciences 15 31158466
2018 Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14. The Journal of biological chemistry 15 30093405
2008 mGluR5-PLCbeta4-PKCbeta2/PKCgamma pathways in hippocampal CA1 pyramidal neurons in pilocarpine model of status epilepticus in mGluR5+/+ mice. Epilepsy research 15 18774262
2008 Loss of Purkinje cells in the PKCgamma H101Y transgenic mouse. Biochemical and biophysical research communications 15 19056342
2020 PKCγ-Mediated Phosphorylation of CRMP2 Regulates Dendritic Outgrowth in Cerebellar Purkinje Cells. Molecular neurobiology 14 32860158
2016 LysoPCs induce Hck- and PKCδ-mediated activation of PKCγ causing p47phox phosphorylation and membrane translocation in neutrophils. Journal of leukocyte biology 14 27531930
2011 SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene. Acta neurologica Scandinavica 14 21434874
2007 Spinocerebellar ataxia 14: novel mutation in exon 2 of PRKCG in a German family. Movement disorders : official journal of the Movement Disorder Society 14 17149711
2006 PKCgamma knockout mouse lenses are more susceptible to oxidative stress damage. The Journal of experimental biology 14 17050852
2024 TRPM2 enhances ischemic excitotoxicity by associating with PKCγ. Cell reports 13 38308841
2023 Non-synonymous SNPs variants of PRKCG and its association with oncogenes predispose to hepatocellular carcinoma. Cancer cell international 13 37344815
2019 PKCγ promotes axonal remodeling in the cortico-spinal tract via GSK3β/β-catenin signaling after traumatic brain injury. Scientific reports 13 31745212
2007 The human protein kinase C gamma gene (PRKCG) as a susceptibility locus for behavioral disinhibition. Addiction biology 13 17508994
2014 The role of Pak-interacting exchange factor-β phosphorylation at serines 340 and 583 by PKCγ in dopamine release. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 25009260
2014 Single-nucleotide polymorphisms of the PRKCG gene and osteosarcoma susceptibility. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 25252845
2013 Inhibition of the PKCγ-ε pathway relieves from meningeal nociception in an animal model: an innovative perspective for migraine therapy? Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 12 23055050
2012 Proteomic analysis of PKCγ-related proteins in the spinal cord of morphine-tolerant rats. PloS one 12 22860055
2006 A Japanese case of SCA14 with the Gly128Asp mutation. Journal of human genetics 12 17024314
2015 Puerarin alleviates noise-induced hearing loss via affecting PKCγ and GABAB receptor expression. Journal of the neurological sciences 11 25592416
2022 The Emerging Key Role of the mGluR1-PKCγ Signaling Pathway in the Pathogenesis of Spinocerebellar Ataxias: A Neurodevelopmental Viewpoint. International journal of molecular sciences 10 36012439
2021 The PKCγ neurons in anterior cingulate cortex contribute to the development of neuropathic allodynia and pain-related emotion. Molecular pain 10 34898326
2015 PKCγ-positive neurons gate light tactile inputs to pain pathway through pERK1/2 neuronal network in trigeminal neuropathic pain model. Journal of oral & facial pain and headache 10 25635962
2011 PKCγ, role in lens differentiation and gap junction coupling. Current eye research 10 21599470
2001 PKCalpha and PKCgamma overexpression causes lentoid body formation in the N/N 1003A rabbit lens epithelial cell line. Molecular vision 10 11436000
2021 Motor Dyscoordination and Alteration of Functional Correlation Between DGKγ and PKCγ in Senescence-Accelerated Mouse Prone 8 (SAMP8). Frontiers in aging neuroscience 9 33584249
2020 PDK1 Regulates the Maintenance of Cell Body and the Development of Dendrites of Purkinje Cells by pS6 and PKCγ. The Journal of neuroscience : the official journal of the Society for Neuroscience 9 32487697
2020 Precise Regulation of the Basal PKCγ Activity by DGKγ Is Crucial for Motor Coordination. International journal of molecular sciences 9 33114041
2016 The interaction of combined effects of the BDNF and PRKCG genes and negative life events in major depressive disorder. Psychiatry research 9 26921055
2015 Genetic variations in the PRKCG gene and osteosarcoma risk in a Chinese population: a case-control study. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 9 25663494
2010 Congo red, an amyloid-inhibiting compound, alleviates various types of cellular dysfunction triggered by mutant protein kinase cγ that causes spinocerebellar ataxia type 14 (SCA14) by inhibiting oligomerization and aggregation. Journal of pharmacological sciences 9 20938103
2003 Effects of prenyl pyrophosphates on the binding of PKCgamma with RACK1. Journal of experimental zoology. Part A, Comparative experimental biology 9 12506405
2009 Experience on the Barnes spatial maze influences PKCgamma levels in the hippocampus. The International journal of neuroscience 8 19466636
2023 Pathogenicity of PKCγ Genetic Variants-Possible Function as a Non-Invasive Diagnostic Biomarker in Ovarian Cancer. Genes 7 36672978
2019 Upregulation of spinal glucose-dependent insulinotropic polypeptide receptor induces membrane translocation of PKCγ and synaptic target of AMPA receptor GluR1 subunits in dorsal horns in a rat model of incisional pain. Neurochemistry international 7 31870892
2013 SCA14 mutation V138E leads to partly unfolded PKCγ associated with an exposed C-terminus, altered kinetics, phosphorylation and enhanced insolubilization. Journal of neurochemistry 7 24134140