Affinage

Showing PRKCG — PKCG is a alias.

PRKCG

Protein kinase C gamma type · UniProt P05129

Length
697 aa
Mass
78.4 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKCG encodes PKCγ, a calcium- and diacylglycerol-dependent serine/threonine kinase that operates as a signaling hub across nociceptive circuits, cerebellar Purkinje cell biology, lens gap-junction control, and several receptor-coupled pathways (PMID:9323205, PMID:32033984). In the spinal dorsal horn, PKCγ marks a discrete population of excitatory lamina II interneurons that receive myelinated, non-nociceptive VGLUT1+ afferent input; this population is dispensable for acute pain but required for injury-induced central sensitization, and when normally silenced by glycinergic inhibition it gates tactile allodynia through an NMDA receptor-dependent local circuit (PMID:9323205, PMID:17987109, PMID:18685019). In cerebellar Purkinje cells, PKCγ activity is set by DGKγ-controlled DAG levels and PDK1-dependent maturation, and is required for climbing-fiber synapse pruning, long-term depression, and dendritic development, in part through phosphorylation of CRMP2 at Thr555 (PMID:32033984, PMID:32487697, PMID:32860158, PMID:21976518). PKCγ also regulates lens intercellular coupling: upon IGF-I or phorbol-ester activation it translocates to membrane/lipid-raft fractions, co-immunoprecipitates with and directly phosphorylates connexins 43, 50, and 46, and reduces gap-junction communication, an output gated by 14-3-3ε binding at the C1B domain (PMID:12601045, PMID:16123426, PMID:15459208). At the mu-opioid receptor, NMDAR/nNOS-generated zinc recruits PKCγ via its C1 cysteine-rich domains to the HINT1/RGSZ complex, where it phosphorylates and desensitizes the receptor and cross-talks with Raf-1 to modulate ERK signaling (PMID:18652891, PMID:21235400). Additional substrate and effector relationships include βPIX phosphorylation driving Cdc42/Rac1-dependent dopamine release, and a Src–PLD1–PKCγ–cPLA2 axis driving VEGF-induced retinal angiogenesis (PMID:25009260, PMID:20421451, PMID:21536681). Missense mutations in the C1 domain cause spinocerebellar ataxia type 14 (SCA14): these mutations misfold PKCγ, cause cytoplasmic mislocalization and amyloid-like aggregation, and produce combined loss- and gain-of-function kinase dysregulation that disrupts Purkinje cell dendritic morphology and function (PMID:30249303, PMID:25217572, PMID:33478986).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established whether PKCγ contributes to acute pain or to injury-induced plasticity, distinguishing a sensitization role from baseline nociception.

    Evidence PKCγ-null mice with behavioral pain testing after partial sciatic nerve section, plus neurochemical mapping to dorsal horn interneurons

    PMID:9323205

    Open questions at the time
    • Did not define the synaptic input or circuit driving PKCγ interneuron activation
    • Downstream phosphorylation substrates in sensitization not identified
  2. 2001 High

    Clarified that PKCγ governs the transition from short- to long-term spinal hyperexcitability but is not the sole determinant of persistent allodynia.

    Evidence Electrophysiology and behavior in wild-type vs. PKCγ-null mice with NMDA receptor antagonists

    PMID:11438608

    Open questions at the time
    • Other NMDA-dependent circuits contributing to allodynia not identified
    • Molecular targets of PKCγ in nociceptive neurons unresolved
  3. 2002 High

    Demonstrated a developmental signaling role by showing PKCγ phosphorylates syndecan-2 to control left-right asymmetry.

    Evidence Phosphorylation assays and dominant-negative/constitutively active constructs in Xenopus embryos

    PMID:12507425

    Open questions at the time
    • Relevance to mammalian development not established
    • Upstream activator of PKCγ in this context unknown
  4. 2005 High

    Linked PKCγ to lens gap-junction regulation by showing direct connexin phosphorylation and raft translocation reduce intercellular coupling.

    Evidence In vitro kinase assays, co-IP, freeze-fracture immunolabeling, and dye-transfer assays in lens cells (Cx43, Cx50, Cx46)

    PMID:12601045 PMID:16123426

    Open questions at the time
    • Phosphosite identity on connexins not fully mapped
    • Physiological significance for lens transparency not directly tested
  5. 2004 High

    Identified 14-3-3ε binding at the C1B domain as an autoregulatory brake on PKCγ activation and gap-junction inhibition.

    Evidence Peptide competition, in vitro/in vivo binding assays, kinase activity and dye-transfer assays with MS mapping

    PMID:15459208

    Open questions at the time
    • Structural basis of the 14-3-3ε/C1B interaction not resolved
    • Whether SCA14 mutations alter 14-3-3ε binding not tested
  6. 2008 High

    Defined the anatomical input to PKCγ interneurons and the receptor-level mechanism at the mu-opioid receptor, connecting circuit and biochemical roles.

    Evidence Tract tracing, immuno-EM, and Fos mapping of dorsal horn; co-IP and antisense knockdown at the MOR with zinc/HINT1 pharmacology

    PMID:18652891 PMID:18685019

    Open questions at the time
    • MOR phosphosites phosphorylated by PKCγ not mapped
    • Quantitative contribution of PKCγ vs other PKCs at MOR not resolved
  7. 2010 Medium

    Placed PKCγ in a VEGF-driven angiogenic cascade downstream of Src–PLD1 and upstream of cPLA2.

    Evidence siRNA, dominant negatives, endothelial functional assays, and in vivo oxygen-induced retinopathy model

    PMID:20421451 PMID:21536681

    Open questions at the time
    • Direct PKCγ substrate linking to cPLA2 not identified
    • Mechanism of PKCγ activation by PLD1-derived lipids not defined
  8. 2011 High

    Established that SCA14 mutant PKCγ acts dominant-negatively in vivo to disrupt cerebellar synaptic plasticity and development.

    Evidence Lentiviral in vivo expression of S119P in Purkinje cells with CF synapse, LTD, and slow-EPSC electrophysiology

    PMID:21976518

    Open questions at the time
    • Reconciliation of dominant-negative effect with later gain-of-function findings not addressed
    • Substrate underlying impaired pruning not identified
  9. 2013 Medium

    Provided a structural mechanism for SCA14 mutations by showing C1B unfolding alters PKCγ translocation kinetics and solubility, rescuable by PDK1.

    Evidence FRET-FLIM in live cells, translocation kinetics, fractionation, and PDK1 co-expression rescue (V138E)

    PMID:24134140

    Open questions at the time
    • Single mutation analyzed by live-cell FRET-FLIM
    • Link between altered conformation and aggregation not directly shown
  10. 2014 High

    Identified PKCγ as intrinsically amyloidogenic and a direct kinase for βPIX, expanding its substrate repertoire and pathogenic potential.

    Evidence In vitro fibril formation with domain mapping; in vitro/in vivo kinase assays and rescue of dopamine release via βPIX site mutants

    PMID:25009260 PMID:25217572

    Open questions at the time
    • Trigger for fibrillization in vivo not established
    • Whether βPIX axis operates beyond PC12 dopamine cells unknown
  11. 2018 High

    Resolved the dual loss/gain-of-function nature of SCA14 in patient-relevant cells and identified Hsp70 as a modifier of mutant PKCγ aggregation.

    Evidence Patient iPSC-derived cells and post-mortem cerebellum with kinase activity assays; co-IP domain mapping and pharmacological Hsp70 induction

    PMID:30093405 PMID:30249303

    Open questions at the time
    • How a single mutation produces both reduced protein and hyperactivity not mechanistically unified
    • Therapeutic durability of Hsp70 induction not established
  12. 2020 High

    Defined the cerebellar regulatory and effector network of PKCγ: DGKγ sets its activity and CRMP2-Thr555 phosphorylation governs Purkinje dendritic development.

    Evidence Purkinje-specific DGKγ KO with PKCγ-inhibitor rescue; IP-MS, PLA, and phospho-mutant CRMP2 knock-in mice

    PMID:32033984 PMID:32860158

    Open questions at the time
    • Full set of PKCγ substrates controlling dendritogenesis not enumerated
    • Quantitative PKCγ activity window for normal development not defined
  13. 2021 High

    Demonstrated that constitutive PKCγ activation alone, independent of protein loss, causes SCA-like Purkinje pathology, and confirmed PKCγ as a PDK1 effector.

    Evidence PKCγ-A24E knock-in mice with kinase activity, morphology, behavior, and RNA profiling; Purkinje-specific PDK1 KO with rAAV-PKCγ rescue

    PMID:32487697 PMID:33478986

    Open questions at the time
    • Pathogenic substrates driven by constitutive activity not pinpointed
    • Relationship between A24E degradation and aggregation pathways unclear
  14. 2024 High

    Identified TRPM2 as a C2-domain physical partner that couples Ca2+ influx to PKCγ activation and excitotoxic NMDAR potentiation in ischemia.

    Evidence Interaction-motif mapping, co-IP, interfering peptide and motif deletion, Ca2+ imaging, NMDAR recordings, and in vivo stroke models

    PMID:38308841

    Open questions at the time
    • PKCγ substrate downstream of TRPM2 coupling not identified
    • Generalizability beyond ischemic neuronal death not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single PKCγ enzyme is differentially activated, localized, and directed toward distinct substrates across pain circuits, Purkinje cells, lens, immune, and tumor contexts remains unresolved.
  • Context-specific scaffolds determining substrate selection not systematically defined
  • Unified mechanism reconciling SCA14 loss- and gain-of-function across mutations not established
  • In vivo connexin and MOR phosphosites not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
14-3-3ΕARHGEF7CRMP2DGKΓGJA1HINT1HSPA1ATRPM2

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PKCγ knockout mice show normal acute pain responses but almost completely fail to develop neuropathic pain after partial sciatic nerve section, and PKCγ is restricted to a subset of dorsal horn interneurons. This identifies PKCγ as a required component of injury-induced central sensitization rather than acute nociception. Genetic knockout (PKCγ-null mice), behavioral pain testing, neurochemical analysis of spinal cord Science High 9323205
2001 PKCγ mediates the transition from short-term to long-term hyperexcitability of lamina V nociresponsive neurons after mustard oil injury, but the persistence of behavioral allodynia involves multiple NMDA-dependent spinal cord circuits beyond PKCγ. Electrophysiology and behavioral testing in wild-type vs. PKCγ-null mice with NMDA receptor antagonists The Journal of neuroscience High 11438608
2002 PKCγ mediates phosphorylation of the cytoplasmic domain of syndecan-2 in right (but not left) animal cap ectodermal cells in Xenopus, and both phosphorylated and nonphosphorylated states of syndecan-2 are required for normal left-right development, establishing PKCγ-dependent inside-out signaling through syndecan-2. Biochemical phosphorylation assays, dominant negative/constitutively active PKCγ constructs, loss-of-function in Xenopus embryos, in vivo labeling Cell High 12507425
2003 PKCγ, activated by IGF-I through DAG increase, translocates to the membrane, co-immunoprecipitates with connexin 43 (Cx43), directly phosphorylates Cx43, and causes a decrease in gap junction communication in lens epithelial cells. Calcium mobilization is not essential for IGF-I-stimulated PKCγ translocation. Western blot, coimmunoprecipitation, in vitro PKC phosphorylation assay, scrape-loading/dye-transfer gap junction assay, confocal microscopy Investigative ophthalmology & visual science High 12601045
2004 PKCγ activity and localization are regulated by its binding to 14-3-3ε at the C1B domain (residues C1B1: 101–112 and C1B5: 141–151). Synthetic peptides corresponding to these regions displace 14-3-3ε from endogenous PKCγ, activate PKCγ, promote its membrane translocation, and inhibit gap junction activity in lens epithelial cells. Peptide competition assays, in vivo/in vitro 14-3-3ε binding assays, PKCγ enzyme activity assay, Western blot, gap junction dye transfer assay, HPLC, MALDI-TOF MS The Journal of biological chemistry High 15459208
2005 PKCγ activation by TPA leads to phosphorylation of Cx50 (at serines and threonines) and Cx46 (at threonines only) in lens fiber cells, accompanied by translocation of PKCγ into lipid raft membrane fractions containing Cx46, Cx50, and caveolin-1, reduction of Cx50 channel density in gap junctions, and uncoupling of the lens cortex. Freeze-fracture immunolabeling (FRIL), Lucifer yellow dye transfer assay, PKCγ activity assay, coimmunoprecipitation, connexin phosphorylation analysis Investigative ophthalmology & visual science High 16123426
2007 Glycine inhibitory dysfunction recruits PKCγ interneurons in the spinal dorsal horn to gate tactile allodynia. Selective inhibition of PKCγ or blockade of NMDA receptors in superficial dorsal horn prevents both circuit activation and allodynia, establishing PKCγ-dependent activation of an excitatory NMDA receptor-dependent local circuit as the mechanism. In vivo electrophysiological recordings, pharmacological inhibition of PKCγ, NMDA receptor blockade, anatomical circuit analysis in rats PloS one High 17987109
2008 PKCγ interneurons in the spinal dorsal horn (lamina II) receive synaptic input from myelinated, non-nociceptive afferents expressing VGLUT1, not from unmyelinated nociceptors. Non-noxious input (walking on rotarod) activates PKCγ interneurons, establishing the anatomical basis for their role in injury-induced allodynia. Transganglionic tract tracing, immunoelectron microscopy double labeling, transneuronal labeling, Fos immunoreactivity The Journal of neuroscience High 18685019
2008 Morphine administration recruits PKCγ (predominantly) to the mu-opioid receptor (MOR) C-terminus via the HINT1/RGSZ complex, where DAG activates PKCγ to phosphorylate the MOR, reducing its signaling strength. PKCγ recruitment requires the C1 cysteine-rich domains (CRDs) of PKCγ, free zinc ions (generated by NMDAR/nNOS activation), HINT1 and RGSZ proteins. Intracerebroventricular administration, co-immunoprecipitation, antisense knockdown of HINT1, pharmacological manipulation (MK801, SNAP, TPEN, phorbol esters), serine phosphorylation assays Cellular signalling Medium 18652891
2009 PKCγ activation in embryonic zebrafish potentiates AMPAR-mediated mEPSCs via an NSF- and PICK1-dependent process requiring DAG, Ca2+, SNARE proteins, and actin polymerization. PKCγ activation is necessary for activity-dependent AMPAR trafficking at developing synapses. Whole-cell patch clamp (mEPSC recording), pharmacological activation of PKCγ with PMA, blocking peptides for NSF/PICK1/GluR2 interaction, latrunculin B, tetanus toxin, APV 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 pharmacological agents, dominant negative mutants, or siRNA significantly attenuates VEGF-induced endothelial cell migration, proliferation, tube formation, and hypoxia-induced retinal neovascularization. siRNA knockdown, dominant negative mutants, pharmacological inhibition, endothelial cell migration/proliferation/tube formation assays, in vivo oxygen-induced retinopathy model Blood Medium 20421451
2011 PKCγ activation is downstream of Src-PLD1 signaling and upstream of cPLA2 phosphorylation and arachidonic acid release in VEGF-induced retinal angiogenesis. Inhibition of PKCγ attenuates cPLA2 phosphorylation and hypoxia-induced retinal neovascularization. siRNA knockdown of pathway components, cPLA2 phosphorylation assays, AA release assay, in vivo oxygen-induced retinopathy model The Journal of biological chemistry Medium 21536681
2011 Mutant PKCγ (S119P) associated with SCA14 aggregates in Purkinje cells in vivo, acts in a dominant-negative manner on wild-type PKCγ, impairs climbing fiber synapse pruning, abolishes LTD expression, and increases slow EPSC amplitude. Mutant PKCγ also decreases the membrane residence time of PKCα after depolarization-induced translocation. Lentiviral in vivo expression in mouse Purkinje cells, electrophysiology (CF synapse recordings, LTD, slow EPSCs), confocal colocalization, GFP imaging The Journal of neuroscience High 21976518
2011 PKCγ is required for ethanol-induced increases in GABA-A receptor α4 subunit surface expression in cultured cortical neurons. PKCβ inhibition had no effect, establishing isoform specificity. PKCγ mediates ethanol's effects on GABA-A receptor composition. siRNA knockdown of PKCγ, surface biotinylation, P2 fractionation, whole-cell patch clamp, PKC activator/inhibitor pharmacology Journal of neurochemistry Medium 21155805
2011 NO-released endogenous zinc ions recruit Raf-1 CRD to HINT1 at the MOR C-terminus, and simultaneously PKCγ CRDs bind HINT1 at the same location. Both Raf-1 and PKCγ bind HINT1 simultaneously, and PKCγ enhances Raf-1 function to intensify MEK/ERK1/2 activation, establishing a NO/zinc-regulated PKCγ–Raf-1 cross-talk at the MOR. Co-immunoprecipitation, intracerebroventricular pharmacology, antisense knockdown, zinc chelation Antioxidants & redox signaling Medium 21235400
2011 PKCγ knockout mice showed reduced late-night activity under daytime restricted feeding, and PKCγ modulates food entrainment at least partly by stabilizing the core clock component BMAL1 and reducing its ubiquitylation in a deubiquitination-dependent manner. PKCγ-null mice, restricted feeding behavior, molecular clock gene analysis, BMAL1 ubiquitylation assay PNAS Medium 23185022
2014 EGF stimulates PKCγ through the PLCγ1-Ca2+-PKCγ pathway to drive Hsp90α plasma membrane translocation and extracellular vesicle release, which facilitates tumor cell motility and metastasis. Blocking Hsp90α with a neutralizing antibody inhibits PKCγ-induced metastasis, establishing PKCγ-induced Hsp90α translocation as required for this pro-metastatic effect. siRNA knockdown of PLCγ1, Ca2+ inhibition, PKCγ overexpression/activation, cell-surface Hsp90α assay, in vitro migration assay, in vivo metastasis model, neutralizing antibody Traffic Medium 24899266
2014 PKCγ is an amyloidogenic protein; it forms amyloid-like fibrils in vitro without denaturants and when overexpressed in cultured cells, via its C1A and kinase domains. SCA14-associated mutations in the C1 domain accelerate amyloid-like fibril formation and aggregate toxicity in neuronal cells. In vitro fibril formation assay, cell culture overexpression, long-term time-lapse imaging, domain truncation analysis Human molecular genetics High 25217572
2014 PKCγ directly phosphorylates βPIX (Pak-interacting exchange factor-β) at Ser583 and indirectly at Ser340, and this phosphorylation is required for Ca2+-evoked dopamine release in PC12 cells. βPIX knockdown reduces dopamine release, and only wild-type βPIX (not Ser340Ala or Ser583Ala mutants) rescues this defect. Double knockdown of Cdc42 and Rac1 also decreases dopamine release, establishing a PKCγ–βPIX–Cdc42/Rac1 axis for dopamine secretion. PKCγ-KO mice, phosphoproteomics, in vitro/in vivo kinase assays, βPIX knockdown, site-directed mutagenesis rescue, Ca2+-evoked dopamine release assay The Journal of neuroscience High 25009260
2016 LysoPCs activate PKCγ in neutrophils via a Hck→PKCδ→PKCγ sequential activation cascade: Hck phosphorylates PKCδ (Tyr311, Tyr525, Thr507), which then activates PKCγ (Tyr514 and Ser phosphorylation); activated PKCγ associates with p47phox, leading to its phosphorylation and membrane translocation. PKCγ KO PMNs fail to prime upon lysoPC stimulation, confirming PKCγ's essential role. Co-immunoprecipitation, FRET, immunoblotting, specific inhibitors, PKCγ KO mice, in vivo TRALI model Journal of leukocyte biology High 27531930
2018 SCA14 mutations in the C1 domain of PKCγ (H36R, H101Q) result in cytoplasmic mislocalization, aggregation, and inefficient degradation of PKCγ in patient iPSC-derived cells and post-mortem cerebellum. Mutant PKCγ is hyper-activated, showing increased substrate phosphorylation, indicating combined loss-of-function and gain-of-function mechanisms. Patient iPSC-derived cells, post-mortem SCA14 cerebellum analysis, immunocytochemistry, PKCγ kinase activity/substrate phosphorylation assays, protein localization Acta neuropathologica communications High 30249303
2018 5-HT2A receptor activation induces morphological reorganization (reduced dendritic arborization, enhanced spine density) specifically in PKCγ+ interneurons in medullary dorsal horn via ERK1/2 phosphorylation, contributing to inflammatory mechanical allodynia. Blocking 5-HT2AR prevents both facial mechanical allodynia and associated PKCγ+ interneuron structural changes. Behavioral testing (CFA model), ex vivo electrophysiology, immunohistochemistry (ERK1/2 phosphorylation), morphological analysis, pharmacological 5-HT2AR blockade/activation The Journal of neuroscience Medium 30355630
2018 Hsp70 binds PKCγ and this interaction is enhanced with SCA14-associated aggregating PKCγ variants, mediated by the kinase domain and C2 domain of PKCγ. Pharmacological induction of Hsp70 (via Hsp90 inhibitors celastrol/herbimycin A) attenuates mutant PKCγ aggregation and apoptotic death in Purkinje cells. Co-immunoprecipitation, domain-mapping, pharmacological Hsp70 induction, primary cultured Purkinje cell analysis, in vivo celastrol administration The Journal of biological chemistry Medium 30093405
2019 PKCγ promotes axonal remodeling and neurite outgrowth through phosphorylation of GSK3β, which stabilizes cytosolic β-catenin and increases GAP43 expression, thus facilitating axonal branching (but not extension). In vivo delivery of constitutively active PKCγ to corticospinal neurons promotes midline crossing and sensorimotor recovery after TBI. Loss/gain-of-function in N2a cells and primary neurons, GSK3β phosphorylation assay, β-catenin expression, GAP43 measurement, rAAV in vivo delivery, behavioral recovery assessment Scientific reports Medium 31745212
2019 ΔNp63α suppresses PKCγ expression via miR-320a. Loss of ΔNp63α reduces miR-320a, elevating PKCγ protein levels and increasing Rac1 phosphorylation at Ser71 and cell invasion. Silencing PKCγ or inhibiting PKC reverses increased Rac1 phosphorylation and invasion, placing PKCγ upstream of Rac1 in an invasion-promoting pathway. siRNA knockdown and overexpression, miR-320a mimic, invasion assays, Western blot, luciferase reporter (implied by context) Cell death & disease Medium 31515469
2020 DGKγ directly interacts with PKCγ and is phosphorylated by PKCγ; DGKγ loss in Purkinje cell-specific KO mice results in upregulated PKCγ activity (without affecting PKCα), impaired cerebellar LTD, and retracted Purkinje cell dendrites. A PKCγ-specific inhibitor rescues LTD in DGKγ KO mice, and TRPC3 is negatively regulated by elevated PKCγ. Purkinje cell-specific DGKγ KO mice, cerebellar motor coordination tests, LTD recording in cerebellar slices, PKCγ activity assay, PKCγ-specific inhibitor rescue, GluR2/GRIP dissociation assay eNeuro High 32033984
2020 PKCγ-mediated phosphorylation of CRMP2 at Thr555 regulates Purkinje cell dendritic outgrowth. Immunoprecipitation-coupled mass spectrometry identified CRMP2 as interacting with constitutively active PKCγ(S361G); increased CRMP2 phosphorylation at Thr555 was confirmed in SCA14 model mice. Phospho-defective T555A-CRMP2 reduces dendritic outgrowth, and dynamic regulation of this phosphorylation by PKCγ is required for correct dendritic development. IP-coupled mass spectrometry, Duolink proximity ligation assay, phospho-CRMP2 immunostaining in SCA14 transgenic mice, miRNA knockdown of CRMP2, phospho-mutant CRMP2 overexpression, T555A knock-in mice Molecular neurobiology High 32860158
2020 Metformin inhibits Hsp90α secretion by activating AMPKα1, which decreases PKCγ kinase activity, reduces Hsp90α phosphorylation, and thereby suppresses its membrane translocation and secretion, inhibiting tumor metastasis. Mass spectrometry of secretome, AMPKα1 manipulation, PKCγ kinase activity assay, Hsp90α phosphorylation measurement, in vitro and in vivo metastasis assays Cells Medium 31936169
2021 A constitutively activating pseudosubstrate domain mutation (A24E) in PKCγ leads to protein dephosphorylation and degradation, dramatically reducing PKCγ protein levels while increasing PKCγ kinase activity. Purkinje cells from these knock-in mice have short thickened dendrites and impaired motor coordination, establishing that constitutive PKCγ activation (not just loss of protein) causes SCA-like pathology. Knock-in mouse model (PKCγ-A24E), PKCγ protein quantification, kinase activity measurement, Purkinje cell dendritic morphology, motor behavior (rotarod), RNA profiling The Journal of neuroscience High 33478986
2021 PDK1 deletion in Purkinje cells reduces PKCγ expression; reintroduction of PKCγ via rAAV rescues the reduced dendritic complexity, establishing PKCγ as a downstream effector of PDK1 in Purkinje cell dendritic development. Purkinje cell-specific PDK1 KO mice (PV-cre or Pcp2-cre), rAAV-PKCγ rescue, dendritic complexity analysis, electrophysiology (spontaneous firing) The Journal of neuroscience Medium 32487697
2024 TRPM2 and PKCγ physically interact via the PKCγ-binding motif on TRPM2 (M2PBM), which directly associates with the C2 domain of PKCγ. TRPM2-mediated Ca2+ influx promotes PKCγ activation, which subsequently enhances TRPM2-mediated potentiation of extrasynaptic NMDAR activity. Disrupting TRPM2-PKCγ coupling (TAT-M2PBM interfering peptide or M2PBM deletion) abolishes both TRPM2-PKCγ and TRPM2-esNMDAR couplings, reducing excitotoxic neuronal death and ischemic brain injury. Identification of interaction motif, co-IP of TRPM2-PKCγ complex, interfering peptide design (TAT-M2PBM), M2PBM deletion, Ca2+ imaging, NMDAR current recordings, in vitro and in vivo ischemic stroke models Cell reports High 38308841
2013 SCA14 mutation V138E causes partial unfolding of the C1B domain and exposure of the PKCγ C-terminus (measured by FRET-FLIM in live cells), leading to faster PMA-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 phenotype. FRET-FLIM in living cells, PMA-induced translocation kinetics, insoluble fraction analysis, PDK1 co-expression rescue Journal of neurochemistry Medium 24134140
2005 The H101Q mutation in PRKCG causes PKCγ loss of stability or solubility in HEK293 cells, leading to time-dependent decreased protein levels and likely decreased PKCγ-dependent phosphorylation, causing slowly progressive cerebellar ataxia (SCA14). HEK293 cell transfection with normal vs. mutant PKCγ, time-dependent protein level assay by Western blot Journal of human genetics Medium 16189624
2010 Mutant PKCγ (SCA14) aggregates are selectively degraded by autophagy. Rapamycin (autophagy inducer) accelerates clearance of mutant PKCγ-GFP aggregates but not wild-type PKCγ-GFP; this effect is absent in Atg5-deficient cells that cannot perform autophagy. Lithium also promotes clearance of mutant PKCγ aggregates. Adenoviral tetracycline-regulated expression system in SH-SY5Y cells, rapamycin/lithium treatment, Atg5-KO mouse embryonic fibroblasts, aggregate clearance quantification Genes to cells Medium 20398063
2008 PKCγ H101Y SCA14 mutation in a transgenic mouse leads to loss of total cellular PKCγ enzyme activity, loss of connexin 57 phosphorylation on serines, activation of caspase-12, and subsequent Purkinje cell loss with motor impairment. Transgenic mouse model, PKCγ enzyme activity assay, Western blot for connexin 57 phosphorylation, caspase-12 activation assay, histology for Purkinje cell loss Biochemical and biophysical research communications Medium 19056342
2015 PKCγ activity in Purkinje cells controls carbonic anhydrase 8 (CA8) expression; CA8 mRNA and protein are strongly induced in PKCγ-S361G SCA14 transgenic Purkinje cells. Overexpression of CA8 in Purkinje cells inhibits dendritic development. However, CA8 knockdown alone does not alter dendritic development and does not protect Purkinje cells from PKCγ-S361G-induced stunted dendrites. No direct binding of CA8 to PKCγ or IP3 receptor was found. Microarray analysis, CA8 overexpression in dissociated cultures, miRNA-mediated knockdown of CA8, PKCγ-S361G transgenic mouse model, cerebellar slice cultures Molecular neurobiology Medium 26399641

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.) 547 9323205
2007 Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PloS one 151 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 144 18685019
2012 Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ-ERK signaling pathway in the developing brain. Brain research 93 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 43 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
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 30 12524182
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
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
2015 Carbonic Anhydrase 8 Expression in Purkinje Cells Is Controlled by PKCγ Activity and Regulates Purkinje Cell Dendritic Growth. Molecular neurobiology 25 26399641
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
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
2015 EphrinB-EphB signaling regulates spinal pain processing via PKCγ. Neuroscience 23 26318332
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
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 Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene. Molecular and cellular neurosciences 16 31158466
2019 ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a. Cell death & disease 16 31515469
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
2019 PKCγ promotes axonal remodeling in the cortico-spinal tract via GSK3β/β-catenin signaling after traumatic brain injury. Scientific reports 14 31745212
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
2007 The human protein kinase C gamma gene (PRKCG) as a susceptibility locus for behavioral disinhibition. Addiction biology 13 17508994
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 12 36012439
2015 Puerarin alleviates noise-induced hearing loss via affecting PKCγ and GABAB receptor expression. Journal of the neurological sciences 12 25592416
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
2024 Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation. Breast cancer research : BCR 10 39039568
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
2022 lncRNA IL-17RA-1 Attenuates LPS-Induced Sepsis via miR-7847-3p/PRKCG-Mediated MAPK Signaling Pathway. Mediators of inflammation 7 36274974
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

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