id: MODULE:camkii_signaling title: CaMKII signaling — calcium/calmodulin activation of the CaMKII holoenzyme, Thr286 autophosphorylation and autonomy, GluN2B docking, CaMKIIN inhibition, and phosphatase termination description: >- Calcium/calmodulin-dependent protein kinase II (CaMKII) is a dodecameric serine/threonine kinase assembled from four paralogous subunits (CaMKII alpha, beta, gamma and delta) that converts transient rises in cytosolic calcium into sustained phosphorylation of target proteins. Calcium-bound calmodulin binds the regulatory segment of each subunit and displaces the autoinhibitory region from the kinase domain. Neighbouring subunits in the holoenzyme then phosphorylate one another on the regulatory threonine (Thr286 in alpha, Thr287 in the other paralogs), which prevents the autoinhibitory region from rebinding and gives Ca2+/calmodulin-independent (autonomous) activity that outlasts the calcium signal. In neurons the activated kinase translocates to the postsynaptic density, where binding to the GluN2B subunit of the NMDA receptor anchors it and itself sustains autonomous activity; there CaMKII phosphorylates AMPA receptor subunits and the auxiliary subunit stargazin during long-term potentiation. In cardiac myocytes CaMKII delta phosphorylates L-type calcium channel subunits, the ryanodine receptor RyR2, phospholamban and the sodium channel Nav1.5, and in the nucleus the class IIa histone deacetylase HDAC4. Activity is limited by the endogenous inhibitor proteins CaMKIIN alpha and beta, which bind only the activated kinase, and is terminated by protein phosphatases (PP1, PP2A and the CaMK phosphatase PPM1F) that dephosphorylate Thr286. status: DRAFT scope: CONCRETE references: - id: PMID:22717267 title: CaMKII regulation in information processing and storage. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified review (Coultrap and Bayer, Trends Neurosci 2012; RGD diagram reference RGD:7240705). Full text cached. Used for Ca2+/CaM activation, T286 autonomy and GluN2B-induced autonomy. - id: PMID:22334212 title: Mechanisms of CaMKII action in long-term potentiation. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified review (Lisman et al., Nat Rev Neurosci 2012; RGD diagram reference RGD:7240704). Full text cached. Used for NR2B binding and the stargazin/GluA1 substrates in LTP. - id: PMID:20668654 title: Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Rellos et al., PLoS Biol 2010; RGD diagram reference RGD:7241023); source of the CaMKII and calmodulin IPI rows in GOA. Used for T287 autonomy. - id: PMID:35568036 title: A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Source of the CALM1 GO:0043539 and CAMK2A GO:0004683 IDA rows; cited only for the statement that Ca2+-calmodulin binds and activates CaMKII. - id: PMID:11459059 title: Interaction with the NMDA receptor locks CaMKII in an active conformation. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Bayer et al., Nature 2001). Abstract only. Regulated CaMKII binding to two NR2B sites drives synaptic translocation and generates autonomous activity. - id: PMID:9724800 title: Characterization of a calmodulin kinase II inhibitor protein in brain. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Chang et al., PNAS 1998). Abstract only. Rat CaM-KIIN (CAMK2N1 ortholog) binds only activated CaMKII and selectively inhibits it. - id: PMID:11502252 title: 'A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly.' reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified review (Lisman and Zhabotinsky, Neuron 2001). Abstract only. Cited for dephosphorylation of CaMKII by postsynaptic-density PP1. - id: PMID:16516168 title: Regulation of CaMKII by alpha4/PP2Ac contributes to learning and memory. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Yamashita et al., Brain Res 2006). Abstract only. CaMKII alpha associates with PP2Ac and alpha4, and neuronal alpha4 loss raises CaMKII activity. - id: PMID:11559703 title: The Caenorhabditis elegans sex-determining protein FEM-2 and its human homologue, hFEM-2, are Ca2+/calmodulin-dependent protein kinase phosphatases that promote apoptosis. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Tan et al., JBC 2001). Abstract only. hFEM-2 (PPM1F) dephosphorylates CaMKII in vitro. - id: PMID:22514276 title: Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates cardiac sodium channel NaV1.5 gating by multiple phosphorylation sites. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Ashpole et al., JBC 2012); full text cached. CaMKII delta C phosphorylates Nav1.5; cited for a cardiac substrate. - id: PMID:16767219 title: CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Backs et al., JCI 2006). Abstract only. CaMKII docks on and phosphorylates HDAC4, driving its nuclear export. evidence: - source_id: PW:0001185 title: calcium/calmodulin dependent kinase 2 signaling pathway statement: >- The module boundary follows the RGD diagram for this Pathway Ontology term: Ca2+ associated with Calm1, Calm2 and Calm3; calmodulin activating Camk2a, Camk2b, Camk2d and Camk2g; Camk2a and Camk2b associated with Grin2b; Camk2n1 and Camk2n2 and the "Camk2 phosphatases" acting negatively on the kinase; Camk2a acting on Gria1 and Cacng2 towards long-term synaptic potentiation; and Camk2d acting on Cacna1c, Cacnb2, Ryr2, Scn5a, Hdac4 and Hdac5 towards excitation-contraction and excitation-transcription coupling. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0001185.yaml). - source_id: GO:0019722 title: calcium-mediated signaling statement: >- The only current GO process for this pathway, recorded as a skos:broadMatch for PW:0001185 in the project's PW-GO mappings and kept out of matching. GO has no CaMKII signaling pathway term (see notes). notes: >- Derived from the RGD Pathway Ontology diagram PW:0001185 (28 RGD-curated human genes) through the RGD_PATHWAY_ONTOLOGY project, where it sits in the no_specific_go_term tier. GO term search. The go-basic release used for validation (2026-07-26) was searched for every term naming calmodulin-dependent kinase, CaMK or CaM kinase signalling. GO:0099004 (calmodulin dependent kinase signaling pathway) is obsolete; its only "consider" target, GO:0061762 CAMKK-AMPK signaling cascade, is the CaMKK beta-AMPK route of modules/ampk_energy_sensing.yaml and is wrong for CaMKII, which CaMKK does not activate. No live process term is specific to CaMKII signalling. The live terms that are specific to it are a molecular function, GO:0004683 calcium/calmodulin-dependent protein kinase activity, which this module uses on the kinase annotons, and a cellular component, GO:0005954 calcium- and calmodulin-dependent protein kinase complex (synonym CaMKII), used as the concept of the holoenzyme node. The module process concept therefore stays at the broad GO:0019722 calcium-mediated signaling, as the project mapping does; a CaMKII signaling pathway term is requested in proposed_new_terms. Molecular functions come from experimental GOA rows checked in QuickGO: calmodulin GO:0043539 protein serine/threonine kinase activator activity (CALM1 IDA, a CALM1 review core function); CaMKII GO:0004683 (CAMK2A and CAMK2D IDA, CAMK2B IDA; CAMK2G has only a NAS row for the parent activity, so its annoton rests on paralogy and the shared holoenzyme); PP2A and PP1 gamma GO:0004722 protein serine/threonine phosphatase activity (PPP2CA IDA, PPP1CC IDA/IMP); PPM1F GO:0004722 (IDA); GRIN2B GO:0004972 NMDA glutamate receptor activity (IDA). CAMK2N1 and CAMK2N2 have no experimental human GOA rows; their GO:0008427 calcium-dependent protein kinase inhibitor activity is authored here from their IBA rows and the rat CaM-KIIN study (PMID:9724800), and is not backed by an experimental GOA row or a gene review. PPM1F carries an IDA row for GO:0033192 calmodulin-dependent protein phosphatase activity. That term means a phosphatase that itself requires calmodulin (calcineurin); PPM1F is a phosphatase of CaM kinases, a PP2C-family enzyme, so the row looks like a reading of its name "Ca2+/calmodulin-dependent protein kinase phosphatase" and is a possible upstream error. The module uses GO:0004722 for it instead. Calmodulin. CALM1, CALM2 and CALM3 encode an identical protein and are one family participant. Calmodulin is the activator, not a substrate: Ca2+-calmodulin binding displaces the autoinhibitory segment. The upstream calcium sources (NMDA receptor and voltage-gated calcium channel influx, IP3 receptor and ryanodine receptor release; see modules/gpcr_plc_calcium_pkc_signaling.yaml calcium_mobilization) are context, not parts. Kinase variants. The four CaMKII genes are a ONE_OR_MORE variant set along the axis of paralog and tissue: alpha and beta dominate in brain (and form heteromers), delta in heart, gamma is broadly expressed. Thr286/287 autophosphorylation (GO:1990443, a CAMK2A review core function) is placed on every paralog because the regulatory segment and its three phosphosites are invariant (PW:0001185 record text). Inhibitory Thr305/306 phosphorylation and its role in long-term depression, and ROS-driven methionine oxidation as a second autonomy route (reversed by methionine sulfoxide reductases), are recorded in prose only. Substrates are targets, not participants. The RGD substrates (GRIA1, CACNG2 for the neuronal paralogs; CACNA1C, CACNB2, RYR2, SCN5A, PLN, HDAC4 and HDAC5 for CaMKII delta) are listed as targets of the kinase function, following the substrate-versus-participant rule: the kinase performs the step, and the channels and transcriptional repressors are what it acts on. Their own activities (channel conduction, deacetylation, MEF2 repression), long-term potentiation, excitation-contraction coupling and excitation-transcription coupling are downstream outputs and outside the module. PLN is on the RGD human gene list though not drawn; it is included as a target because the record text names it as a CaMKII substrate. Anchoring. GRIN2B is the one anchoring partner modelled, because RGD draws it and its binding both targets the kinase to the synapse and generates autonomous activity (PMID:11459059). Its annoton keeps its experimental molecular function, NMDA glutamate receptor activity, because no experimental GOA row records the CaMKII-binding activity itself; the docking is described in the role description and the connection, not asserted as a GO function. GRIN1, the obligatory NMDA receptor partner, and GRIN2A are on the RGD human list but not drawn, and are mentioned here only. The other RGD "Camk2 partners" (LRRC7/densin-180, DLG1, SYNGAP1) are left out: the record text says their functional role is less well established, and SYNGAP1 is itself a CaMKII substrate. Regulation. CAMK2N1 and CAMK2N2 inhibit only the activated kinase (PMID:9724800); they are an optional regulatory part. Termination is by phosphatases that remove the Thr286 phosphate: PSD PP1 (PMID:11502252; PPP1CC is the RGD gene), cytosolic PP2A (PMID:16516168), and the CaMK phosphatase PPM1F (PMID:11559703). PPM1E (CaMKP-N), also on the RGD list, acts mainly on nuclear CaMKI/CaMKIV and is mentioned only. Calcineurin acts only indirectly, through inhibitor-1 and PP1, and is not a member. GO-CAM grounding. The calmodulin activator and CAMK2A kinase annotons are linked to the human model gomodel:62b4ffe300004489, where CALM1 kinase activator activity directly positively regulates CAMK2A calcium/calmodulin-dependent protein kinase activity in an interferon-gamma context (the seed's best_gocam lead; the activities match even though the biological context differs). The GRIN2B annoton is linked to the NMDA receptor model gomodel:66c7d41500000672. No cached GO-CAM models CaMKII paralogs beta, gamma or delta, CaMKIIN, or CaMKII dephosphorylation. CAMK2B, CAMK2G, CAMK2D, CAMK2N1, CAMK2N2, GRIN2B, PPP1CC and PPM1F have no gene review yet; that is curation follow-up for the project plan. proposed_new_terms: - proposed_name: CaMKII signaling pathway proposed_definition: >- A calcium-mediated signaling pathway in which calcium-bound calmodulin binds and activates the calcium/calmodulin-dependent protein kinase II (CaMKII) holoenzyme, which autophosphorylates (Thr286 in CAMK2A) to become partly calcium-independent and phosphorylates downstream targets, ending with the regulation of a downstream cellular process. justification: >- No live GO process term is specific to CaMKII signalling. GO:0061762 CAMKK-AMPK signaling cascade is a different route, and the module concept stays at the broad GO:0019722 calcium-mediated signaling. proposed_parent: id: GO:0019722 label: calcium-mediated signaling supported_by: - reference_id: PMID:22717267 supporting_text: The Ca(2+)/Calmodulin(CaM)-dependent protein kinase II (CaMKII) is activated by Ca(2+)/CaM - reference_id: PMID:22717267 supporting_text: becomes partially autonomous (Ca(2+)-independent) upon autophosphorylation at T286 module: id: camkii_signaling label: CaMKII signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: calcium-mediated signaling term: id: GO:0019722 label: calcium-mediated signaling description: >- Broad GO process; GO has no live CaMKII signaling pathway term (GO:0099004 is obsolete). The module is the calmodulin-CaMKII branch of calcium signalling. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the diagram is RGD's rat curation and the pathway is conserved across metazoans. cellular_components: - preferred_term: cytosol term: id: GO:0005829 label: cytosol description: Calmodulin binding and CaMKII activation occur in the cytosol. - preferred_term: postsynaptic density term: id: GO:0014069 label: postsynaptic density description: Neuronal CaMKII translocates to the postsynaptic density and binds GluN2B. parts: - order: 1 role: calcium sensing by calmodulin and kinase activation node: id: camkii_calmodulin label: Ca2+-calmodulin activates CaMKII module_type: REGULATORY_STEP description: >- Calcium-bound calmodulin binds the CaMKII regulatory segment and displaces the autoinhibitory region from the kinase domain. annotons: - id: calmodulin_activator label: Calmodulin protein serine/threonine kinase activator activity participant: selector_type: FAMILY family: preferred_term: calmodulin (CALM1, CALM2, CALM3; identical protein) representative_members: - preferred_term: CALM1 term: id: UniProtKB:P0DP23 label: Calmodulin-1 - preferred_term: CALM2 term: id: UniProtKB:P0DP24 label: Calmodulin-2 - preferred_term: CALM3 term: id: UniProtKB:P0DP25 label: Calmodulin-3 function: preferred_term: protein serine/threonine kinase activator activity term: id: GO:0043539 label: protein serine/threonine kinase activator activity targets: - preferred_term: CaMKII alpha term: id: UniProtKB:Q9UQM7 label: Calcium/calmodulin-dependent protein kinase type II subunit alpha - preferred_term: CaMKII delta term: id: UniProtKB:Q13557 label: Calcium/calmodulin-dependent protein kinase type II subunit delta locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- The calcium sensor and activator; it binds Ca2+ through its EF hands and then binds and activates each CaMKII subunit. Not a substrate of the kinase. evidence: - source_id: PMID:35568036 statement: Ca2+-bound calmodulin binds and activates CaMKII. supporting_text: >- When bound to Ca2+, CaM adopts an open conformation facilitating its binding to, and activation of, a large number of downstream targets including calmodulin kinase II (CaMKII). - source_id: PMID:22717267 statement: CaMKII is activated by Ca2+/CaM. supporting_text: >- The Ca(2+)/Calmodulin(CaM)-dependent protein kinase II (CaMKII) is activated by Ca(2+)/CaM gocam_associations: - model: gomodel:62b4ffe300004489 activity: gomodel:62b4ffe300004489/62b4ffe300004590 title: Regulation of the JAK-STAT pathway by calmodulin in response to interferon-gamma (Human) description: >- CALM1 with the same molecular function (GO:0043539), directly positively regulating CAMK2A in the model. - order: 2 role: CaMKII holoenzyme activity and Thr286 autophosphorylation node: id: camkii_holoenzyme label: CaMKII holoenzyme kinase activity and autonomy module_type: PROTEIN_COMPLEX description: >- Dodecameric holoenzyme of CaMKII subunits. Once activated by Ca2+-calmodulin, neighbouring subunits phosphorylate Thr286/287 in trans, giving autonomous activity after calcium falls, and the kinase phosphorylates its channel, receptor and transcriptional-repressor targets. concepts: - preferred_term: calcium- and calmodulin-dependent protein kinase complex term: id: GO:0005954 label: calcium- and calmodulin-dependent protein kinase complex description: The CaMKII holoenzyme (GO synonym CaMKII). evidence: - source_id: PMID:22717267 statement: CaMKII becomes partially autonomous upon T286 autophosphorylation. supporting_text: >- becomes partially autonomous (Ca(2+)-independent) upon autophosphorylation at T286 - source_id: PMID:20668654 statement: Phosphorylated T287 releases a fully active, Ca2+/CaM-independent kinase domain. supporting_text: >- Once T287 has been phosphorylated, the kinase domain is released fully active and independent of Ca2+/CaM, and with its substrate binding site accessible. variant_sets: - id: camkii_paralogs label: CaMKII subunit paralogs axis: paralog and tissue distribution selection: ONE_OR_MORE notes: >- Alpha and beta dominate in brain and co-assemble into heteromers; delta dominates in heart; gamma is broadly expressed. A holoenzyme may contain more than one paralog. variants: - id: camk2a_variant label: CaMKII alpha module_type: REGULATORY_STEP description: >- Brain-enriched subunit; with beta forms the neuronal holoenzyme that drives early LTP. annotons: - id: camk2a_variant_kinase label: CAMK2A calcium/calmodulin-dependent protein kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CAMK2A term: id: UniProtKB:Q9UQM7 label: Calcium/calmodulin-dependent protein kinase type II subunit alpha function: preferred_term: calcium/calmodulin-dependent protein kinase activity term: id: GO:0004683 label: calcium/calmodulin-dependent protein kinase activity targets: - preferred_term: GRIA1 (GluA1) term: id: UniProtKB:P42261 label: Glutamate receptor 1 - preferred_term: CACNG2 (stargazin) term: id: UniProtKB:Q9Y698 label: Voltage-dependent calcium channel gamma-2 subunit processes: - preferred_term: peptidyl-threonine autophosphorylation term: id: GO:1990443 label: peptidyl-threonine autophosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Neuronal CaMKII subunit; autophosphorylates Thr286, docks on GluN2B and phosphorylates GluA1 and stargazin. evidence: - source_id: PMID:22334212 statement: >- CaMKII phosphorylates the AMPA receptor auxiliary subunit stargazin, which lets the receptors bind PSD-95. supporting_text: >- This phosphorylation occurs on the AMPAR auxiliary protein stargazin and allows the receptors to bind to PSD-95 gocam_associations: - model: gomodel:62b4ffe300004489 activity: gomodel:62b4ffe300004489/62b4ffe300004580 title: Regulation of the JAK-STAT pathway by calmodulin in response to interferon-gamma (Human) description: >- Same gene and molecular function (GO:0004683), activated by CALM1 in the model; the model's context is interferon-gamma signalling to STAT1. - id: camk2b_variant label: CaMKII beta module_type: REGULATORY_STEP description: >- Brain-enriched subunit that co-assembles with alpha; RGD associates it with GluN2B. annotons: - id: camk2b_variant_kinase label: CAMK2B calcium/calmodulin-dependent protein kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CAMK2B term: id: UniProtKB:Q13554 label: Calcium/calmodulin-dependent protein kinase type II subunit beta function: preferred_term: calcium/calmodulin-dependent protein kinase activity term: id: GO:0004683 label: calcium/calmodulin-dependent protein kinase activity targets: - preferred_term: GRIA1 (GluA1) term: id: UniProtKB:P42261 label: Glutamate receptor 1 - preferred_term: CACNG2 (stargazin) term: id: UniProtKB:Q9Y698 label: Voltage-dependent calcium channel gamma-2 subunit processes: - preferred_term: peptidyl-threonine autophosphorylation term: id: GO:1990443 label: peptidyl-threonine autophosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Neuronal CaMKII subunit; autophosphorylates Thr287 and docks on GluN2B with alpha. - id: camk2d_variant label: CaMKII delta module_type: REGULATORY_STEP description: >- Cardiac-enriched subunit; a splice form with a nuclear localization signal reaches HDAC4. annotons: - id: camk2d_variant_kinase label: CAMK2D calcium/calmodulin-dependent protein kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CAMK2D term: id: UniProtKB:Q13557 label: Calcium/calmodulin-dependent protein kinase type II subunit delta function: preferred_term: calcium/calmodulin-dependent protein kinase activity term: id: GO:0004683 label: calcium/calmodulin-dependent protein kinase activity targets: - preferred_term: CACNA1C (Cav1.2) term: id: UniProtKB:Q13936 label: Voltage-dependent L-type calcium channel subunit alpha-1C - preferred_term: CACNB2 term: id: UniProtKB:Q08289 label: Voltage-dependent L-type calcium channel subunit beta-2 - preferred_term: RYR2 term: id: UniProtKB:Q92736 label: Ryanodine receptor 2 - preferred_term: SCN5A (Nav1.5) term: id: UniProtKB:Q14524 label: Sodium channel protein type 5 subunit alpha - preferred_term: PLN (phospholamban) term: id: UniProtKB:P26678 label: Phospholamban - preferred_term: HDAC4 term: id: UniProtKB:P56524 label: Histone deacetylase 4 - preferred_term: HDAC5 term: id: UniProtKB:Q9UQL6 label: Histone deacetylase 5 processes: - preferred_term: peptidyl-threonine autophosphorylation term: id: GO:1990443 label: peptidyl-threonine autophosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Cardiac CaMKII; phosphorylates L-type calcium channel subunits, RyR2, Nav1.5, phospholamban and the class IIa HDACs. evidence: - source_id: PMID:22514276 statement: CaMKII delta C phosphorylates the Nav1.5 domain I-II loop at Ser516 and Thr594. supporting_text: >- This region was also phosphorylated by δ(C)-CaMKII, specifically at the Ser-516 and Thr-594 sites. - source_id: PMID:16767219 statement: CaMKII phosphorylation of HDAC4 drives its nuclear export, derepressing target genes. supporting_text: >- Phosphorylation of HDAC4 by CaMKII promotes nuclear export and prevents nuclear import of HDAC4, with consequent derepression of HDAC target genes. - id: camk2g_variant label: CaMKII gamma module_type: REGULATORY_STEP description: >- Broadly expressed subunit at lower levels; no specific substrates are drawn by RGD. annotons: - id: camk2g_variant_kinase label: CAMK2G calcium/calmodulin-dependent protein kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CAMK2G term: id: UniProtKB:Q13555 label: Calcium/calmodulin-dependent protein kinase type II subunit gamma function: preferred_term: calcium/calmodulin-dependent protein kinase activity term: id: GO:0004683 label: calcium/calmodulin-dependent protein kinase activity processes: - preferred_term: peptidyl-threonine autophosphorylation term: id: GO:1990443 label: peptidyl-threonine autophosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Ubiquitous CaMKII subunit; its activity rests on paralogy and the shared regulatory segment (only a NAS GOA row). - order: 3 role: GluN2B docking and synaptic anchoring (neuronal) optional: true node: id: camkii_glun2b_docking label: GluN2B docking anchors CaMKII at the synapse module_type: REGULATORY_STEP description: >- Activated CaMKII binds the GluN2B carboxy-terminal tail of the NMDA receptor, which translocates it to the postsynaptic density and locks it in an autonomously active conformation independently of Thr286. annotons: - id: grin2b_docking label: GluN2B NMDA receptor subunit docking CaMKII participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRIN2B (GluN2B) term: id: UniProtKB:Q13224 label: Glutamate receptor ionotropic, NMDA 2B function: preferred_term: NMDA glutamate receptor activity term: id: GO:0004972 label: NMDA glutamate receptor activity locations: - preferred_term: postsynaptic density term: id: GO:0014069 label: postsynaptic density role_description: >- NMDA receptor subunit whose channel admits the calcium that activates neuronal CaMKII and whose cytoplasmic tail docks the activated kinase. The docking, not the channel activity, is the role modelled here; the GO function is its experimental one because no GOA row records the CaMKII-binding activity. evidence: - source_id: PMID:11459059 statement: >- Regulated CaMKII binding to two NR2B sites mediates glutamate-induced translocation of the kinase to the synapse. supporting_text: >- regulated CaMKII interaction with two sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons - source_id: PMID:22717267 statement: GluN2B binding is a second mechanism that generates autonomous CaMKII activity. supporting_text: CaMKII binding to the NMDAR subunit GluN2B gocam_associations: - model: gomodel:66c7d41500000672 activity: gomodel:66c7d41500000672/66c7d41500000686 title: NMDA glutamate receptor activity co-activated by glycine and involving GRIN1 and GRIN2B (Human) description: Same gene and molecular function (GO:0004972); the model does not include CaMKII. - order: 4 role: endogenous CaMKIIN inhibition (regulation) optional: true node: id: camkii_inhibitor_proteins label: CaMKIIN inhibitor proteins module_type: REGULATORY_STEP description: >- Small proteins that bind the catalytic domain of activated (Ca2+/CaM-bound or autophosphorylated) CaMKII and inhibit it selectively. annotons: - id: camk2n_inhibitors label: CaMKIIN calcium-dependent protein kinase inhibitor activity participant: selector_type: FAMILY family: preferred_term: CaMKII inhibitor proteins (CAMK2N1, CAMK2N2) representative_members: - preferred_term: CAMK2N1 (CaMKIIN alpha) term: id: UniProtKB:Q7Z7J9 label: Calcium/calmodulin-dependent protein kinase II inhibitor 1 - preferred_term: CAMK2N2 (CaMKIIN beta) term: id: UniProtKB:Q96S95 label: Calcium/calmodulin-dependent protein kinase II inhibitor 2 function: preferred_term: calcium-dependent protein kinase inhibitor activity term: id: GO:0008427 label: calcium-dependent protein kinase inhibitor activity locations: - preferred_term: synapse term: id: GO:0045202 label: synapse role_description: >- Steric inhibitors specific for the activated kinase; their physiological role is not settled. Function authored from IBA rows and the rat protein (see notes). evidence: - source_id: PMID:9724800 statement: >- Rat CaM-KIIN binds the CaMKII catalytic domain, inhibits it potently and selectively, and interacts only with activated CaMKII. supporting_text: >- CaM-KIIN interacted only with activated CaM-KII (i. e., in the presence of Ca2+/CaM or after autophosphorylation) - order: 5 role: dephosphorylation and termination node: id: camkii_phosphatases label: Phosphatases dephosphorylate CaMKII Thr286 module_type: REGULATORY_STEP description: >- Protein phosphatases remove the Thr286 phosphate and return CaMKII to the calcium-dependent state: PP1 in the postsynaptic density, PP2A in the cytosol, and the CaMK phosphatase PPM1F. variant_sets: - id: camkii_thr286_phosphatase label: CaMKII Thr286 phosphatase axis: phosphatase family and compartment (PPP-family PP1 at the postsynaptic density, PPP-family PP2A in the cytosol, PPM-family PPM1F) selection: ONE_OR_MORE variants: - id: pp1_variant label: PP1 (postsynaptic density) module_type: REACTION annotons: - id: camkii_pp1_phosphatase label: PP1 dephosphorylation of CaMKII participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP1CC (PP1 gamma catalytic subunit) term: id: UniProtKB:P36873 label: Serine/threonine-protein phosphatase PP1-gamma catalytic subunit function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity targets: - preferred_term: CaMKII alpha (phospho-Thr286) term: id: UniProtKB:Q9UQM7 label: Calcium/calmodulin-dependent protein kinase type II subunit alpha processes: - preferred_term: protein dephosphorylation term: id: GO:0006470 label: protein dephosphorylation locations: - preferred_term: postsynaptic density term: id: GO:0014069 label: postsynaptic density role_description: >- PPP-family phosphatase that dephosphorylates autophosphorylated CaMKII in the postsynaptic density. Calcineurin acts only indirectly (through inhibitor-1 and PP1) and is not a member. evidence: - source_id: PMID:11502252 statement: CaMKII autophosphorylation is reversed by postsynaptic-density PP1. supporting_text: >- its dephosphorylation by PSD protein phosphatase-1 (PP1) - id: pp2a_variant label: PP2A (cytosol) module_type: REACTION annotons: - id: camkii_pp2a_phosphatase label: PP2A dephosphorylation of CaMKII participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPP2CA (PP2A catalytic subunit alpha) term: id: UniProtKB:P67775 label: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity targets: - preferred_term: CaMKII alpha (phospho-Thr286) term: id: UniProtKB:Q9UQM7 label: Calcium/calmodulin-dependent protein kinase type II subunit alpha processes: - preferred_term: protein dephosphorylation term: id: GO:0006470 label: protein dephosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- PPP-family phosphatase whose catalytic subunit associates with CaMKII alpha in the cytosol. evidence: - source_id: PMID:16516168 statement: CaMKII alpha associates with the PP2A catalytic subunit and its regulator alpha4. supporting_text: >- CaMKIIalpha was associated with the catalytic subunit of PP2A (PP2Ac) and alpha4, a regulator of PP2A - id: ppm1f_variant label: PPM1F (CaMK phosphatase) module_type: REACTION annotons: - id: camkii_ppm1f_phosphatase label: PPM1F dephosphorylation of CaMKII participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PPM1F (CaMKPase, hFEM-2) term: id: UniProtKB:P49593 label: Protein phosphatase 1F function: preferred_term: protein serine/threonine phosphatase activity term: id: GO:0004722 label: protein serine/threonine phosphatase activity targets: - preferred_term: CaMKII alpha (phospho-Thr286) term: id: UniProtKB:Q9UQM7 label: Calcium/calmodulin-dependent protein kinase type II subunit alpha processes: - preferred_term: protein dephosphorylation term: id: GO:0006470 label: protein dephosphorylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- PPM-family (PP2C-type, metal-dependent) phosphatase, structurally unrelated to PP1 and PP2A, that dephosphorylates CaM kinases. evidence: - source_id: PMID:11559703 statement: hFEM-2 (PPM1F) dephosphorylates CaMKII efficiently in vitro. supporting_text: >- hFEM-2 and FEM-2, but not PP2Calpha, were demonstrated to dephosphorylate CaM kinase II efficiently in vitro connections: - source: camkii_calmodulin target: camkii_holoenzyme connection_type: POSITIVELY_REGULATES description: Ca2+-calmodulin binding displaces the autoinhibitory segment and activates the kinase. - source: camkii_glun2b_docking target: camkii_holoenzyme connection_type: POSITIVELY_REGULATES description: >- GluN2B binding anchors CaMKII at the synapse and holds it autonomously active independent of Thr286 phosphorylation. - source: camkii_inhibitor_proteins target: camkii_holoenzyme connection_type: NEGATIVELY_REGULATES description: CaMKIIN proteins bind and inhibit the activated kinase. - source: camkii_phosphatases target: camkii_holoenzyme connection_type: NEGATIVELY_REGULATES description: Dephosphorylation of Thr286 ends autonomous activity.