Details for: CAMK2A

Gene ID: 815

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CAMK2A

Ensembl ID: ENSG00000070808

Description: calcium/calmodulin dependent protein kinase II alpha

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 33.44
    rCSI 72.54%
    PRS 99.48
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 29.03
    rCSI 70.56%
    PRS 99.12
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 23.16
    rCSI 55.39%
    PRS 99.48
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 21.48
    rCSI 70.6%
    PRS 99.33
  • L6b glutamatergic cortical neuron CL4023038
    CSI 21.35
    rCSI 66.71%
    PRS 99.42
  • VIP GABAergic cortical interneuron CL4023016
    CSI 19.57
    rCSI 23.38%
    PRS 99.45
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 18.62
    rCSI 67%
    PRS 99.25
  • sst GABAergic cortical interneuron CL4023017
    CSI 18.4
    rCSI 23.73%
    PRS 99.62
  • inhibitory interneuron CL0000498
    CSI 16.89
    rCSI 38.99%
    PRS 99.62
  • cerebral cortex endothelial cell CL1001602
    CSI 15.9
    rCSI 27.5%
    PRS 99.69
  • neural cell CL0002319
    CSI 15.6
    rCSI 58.87%
    PRS 99.21
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 14.69
    rCSI 55.53%
    PRS 99.22
  • astrocyte of the cerebral cortex CL0002605
    CSI 13.56
    rCSI 30.4%
    PRS 99.42
  • sncg GABAergic cortical interneuron CL4023015
    CSI 12.35
    rCSI 19.86%
    PRS 99.33
  • cerebral cortex neuron CL0010012
    CSI 11.53
    rCSI 46.98%
    PRS 99.58
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 11.28
    rCSI 66.43%
    PRS 99.34
  • pericyte CL0000669
    CSI 11.04
    rCSI 29.39%
    PRS 94.77
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 11.03
    rCSI 13.72%
    PRS 99.39
  • glutamatergic neuron CL0000679
    CSI 10.69
    rCSI 21.96%
    PRS 98.55
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 10.49
    rCSI 18.52%
    PRS 99.41
  • vascular leptomeningeal cell CL4023051
    CSI 8.58
    rCSI 15.04%
    PRS 99.79
  • amacrine cell CL0000561
    CSI 8.57
    rCSI 24.84%
    PRS 99.6
  • mature astrocyte CL0002627
    CSI 8.17
    rCSI 34.74%
    PRS 99.84
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 7.98
    rCSI 24.97%
    PRS 99.55
  • neuron CL0000540
    CSI 7.34
    rCSI 19.55%
    PRS 99.25
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 7.12
    rCSI 11.95%
    PRS 99.5
  • serotonergic neuron CL0000850
    CSI 5.29
    rCSI 23.61%
    PRS 98.9
  • medium spiny neuron CL1001474
    CSI 5.02
    rCSI 43.27%
    PRS 99.58
  • dopaminergic neuron CL0000700
    CSI 4.99
    rCSI 28.18%
    PRS 99.27
  • GABAergic neuron CL0000617
    CSI 4.13
    rCSI 13.85%
    PRS 98.38
  • central nervous system neuron CL2000029
    CSI 3.8
    rCSI 27.92%
    PRS 99.66
  • glycinergic amacrine cell CL4030028
    CSI 3.49
    rCSI 9.1%
    PRS 99.53
  • GABAergic amacrine cell CL4030027
    CSI 3.47
    rCSI 11.87%
    PRS 99.35
  • cardiac muscle cell CL0000746
    CSI 3.44
    rCSI 4.93%
    PRS 99.25
  • direct pathway medium spiny neuron CL4023026
    CSI 2.65
    rCSI 63.52%
    PRS 98.81
  • indirect pathway medium spiny neuron CL4023029
    CSI 2.52
    rCSI 60.81%
    PRS 98.74

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [CAMK2A](/details-gene/815) encodes the alpha subunit of the calcium/calmodulin-dependent protein kinase II (CaMKII), a critical serine/threonine protein kinase. This enzyme is a key mediator of calcium signaling in cells and is particularly abundant in the nervous system. **Overall**, expression data reveals that [CAMK2A](/details-gene/815) is a defining marker for multiple subtypes of excitatory and inhibitory neurons within the cerebral cortex, including [L2/3 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4030059) and [VIP GABAergic cortical interneuron](/details-cell/CL4023016). Its function is central to synaptic plasticity, memory formation, and neurotransmitter regulation. Clinically, mutations in [CAMK2A](/details-gene/815) are associated with severe neurodevelopmental disorders, including intellectual disability and seizures ([114078](https://omim.org/entry/114078)), underscoring its indispensable role in proper brain function and development. ## Cellular Roles and Expression Landscape The expression profile of [CAMK2A](/details-gene/815) demonstrates its profound importance within the central nervous system, where it acts as a highly significant marker for a diverse array of neuronal populations. **Overall**, the gene shows its highest significance in glutamatergic excitatory neurons across various cortical layers, including [L2/3 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4030059) (CSI: 33.44), [L4 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4030063) (CSI: 23.16), and [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) (CSI: 18.62). This suggests a fundamental role in establishing and modulating excitatory circuits. Beyond this, [CAMK2A](/details-gene/815) is also significantly expressed in various inhibitory interneuron subtypes, such as [VIP GABAergic cortical interneuron](/details-cell/CL4023016) (CSI: 19.57) and [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 18.40), indicating its function extends to the regulation of inhibitory signaling and the maintenance of network balance. The gene's notable expression in non-neuronal cells like [astrocyte of the cerebral cortex](/details-cell/CL0002605) (CSI: 13.56) and [cerebral cortex endothelial cell](/details-cell/CL1001602) (CSI: 15.90) points to broader roles in glial function and neurovascular coupling. This widespread yet neuron-centric expression pattern solidifies its status as a central player in cortical information processing. ## Pathways and Molecular Function The molecular functions of [CAMK2A](/details-gene/815) are intrinsically linked to its role as a calcium-sensitive kinase. Its primary activities include [calcium/calmodulin-dependent protein kinase activity](/details-go/GO:0004683), [ATP binding](/details-go/GO:0005524), and subsequent [protein phosphorylation](/details-go/GO:0006468). These core functions enable its participation in a vast range of biological processes. Consistent with its high expression in neurons, [CAMK2A](/details-gene/815) is integral to processes governing synaptic function, such as [regulation of neuronal synaptic plasticity](/details-go/GO:0048168), [dendritic spine development](/details-go/GO:0060996), and [regulation of neurotransmitter secretion](/details-go/GO:0046928). Its localization to the [postsynaptic density](/details-go/GO:0014069) is critical for its function. Reactome pathway analysis further clarifies this, highlighting its involvement in [Neuronal System](/details-reactome/R-HSA-112316), particularly in [Activation of nmda receptors and postsynaptic events](/details-reactome/R-HSA-442755) and [Long-term potentiation](/details-reactome/R-HSA-9620244), a cellular mechanism for learning and memory [Link](https://doi.org/10.1016/j.neuron.2004.08.003). Beyond its canonical neuronal roles, functional annotations suggest a broader signaling involvement. [CAMK2A](/details-gene/815) participates in the [Cytokine signaling in immune system](/details-reactome/R-HSA-1280215) pathway, including [Interferon gamma signaling](/details-reactome/R-HSA-877300). Research has demonstrated a requirement for CaMKII in Stat1 phosphorylation following IFN-gamma stimulation [Link](https://doi.org/10.1073/pnas.052159099), and more recently, its role in calcium signaling has been implicated in the host response to bacterial virulence factors [Link](https://doi.org/10.1016/j.cell.2022.04.028). ## Research Directions The well-established role of [CAMK2A](/details-gene/815) in synaptic function and its strong association with neurodevelopmental disorders provide a fertile ground for future investigation. **Proposed Hypotheses:** 1. Given that *de novo* mutations in [CAMK2A](/details-gene/815) cause intellectual disability [Link](https://doi.org/10.1016/j.ajhg.2017.10.003), specific patient-derived missense mutations may act as dominant-negatives, disrupting the assembly of CaMKII holoenzymes in [L2/3 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4030059)s. This could lead to impaired dendritic spine maturation ([GO:0060996](/details-go/GO:0060996)) and abnormal cortical circuit formation, phenocopying the observed patient symptoms. 2. The established link between [CAMK2A](/details-gene/815) and interferon signaling pathways suggests a novel neuroinflammatory role. It is hypothesized that in [astrocyte of the cerebral cortex](/details-cell/CL0002605)s, [CAMK2A](/details-gene/815) kinase activity is a necessary downstream event for type II interferon-mediated inflammatory gene expression. Dysregulation of this process may contribute to the pathology of neuroinflammatory diseases by altering glial support functions. **Experimental Approach:** To test the first hypothesis, one could utilize CRISPR-Cas9 to introduce a specific, clinically-identified missense mutation into human induced pluripotent stem cells (iPSCs). These iPSCs would then be differentiated into cortical organoids or 2D neuronal cultures enriched for [L2/3 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4030059)s. The impact of the mutation would be assessed by comparing mutant and isogenic control neurons. Key assays would include super-resolution microscopy to quantify dendritic spine density and morphology, and multi-electrode array (MEA) recordings to measure deficits in synaptic activity and network-level long-term potentiation. **Therapeutic Potential:** [CAMK2A](/details-gene/815) presents a challenging but important therapeutic target. Since homozygous loss-of-function mutations cause severe disease phenotypes like growth delay and seizures [Link](https://doi.org/10.7554/elife.32451), therapeutic strategies would likely focus on **activation** or restoration of function rather than inhibition. For diseases caused by haploinsufficiency, gene replacement therapy using AAV vectors could be a viable, albeit complex, strategy. For dominant-negative mutations, small molecule stabilizers or chaperones designed to promote proper holoenzyme formation could be explored. However, given its central and widespread role in neuronal signaling, any intervention would require exquisite specificity to avoid widespread, off-target neurological side effects.

Genular Protein ID: 3508354350

Symbol: KCC2A_HUMAN

Name: Calcium/calmodulin-dependent protein kinase type II subunit alpha

UniProtKB Accession Codes:

Q9UQM7 Q9UL21 Q9Y2H4 Q9Y352

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CORUM 1 CTD 1 ChEBI 13 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 DrugCentral 1 EC 2 EMBL 4 EMDB 2 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 41 Gene3D 3 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 5 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 21 PDBsum 21 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 21 RefSeq 1 Rhea 6 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10231032

Title: Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.

PubMed ID: 10231032

DOI: 10.1093/dnares/6.1.63

PubMed ID: 15372022

Title: The DNA sequence and comparative analysis of human chromosome 5.

PubMed ID: 15372022

DOI: 10.1038/nature02919

PubMed ID: 11972023

Title: Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-gamma.

PubMed ID: 11972023

DOI: 10.1073/pnas.052159099

PubMed ID: 14722083

Title: Comparative analyses of the three-dimensional structures and enzymatic properties of alpha, beta, gamma and delta isoforms of Ca2+-calmodulin-dependent protein kinase II.

PubMed ID: 14722083

DOI: 10.1074/jbc.m313597200

PubMed ID: 15312654

Title: SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation.

PubMed ID: 15312654

DOI: 10.1016/j.neuron.2004.08.003

PubMed ID: 23805378

Title: CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16.

PubMed ID: 23805378

DOI: 10.7554/elife.00518

PubMed ID: 28130356

Title: Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.

PubMed ID: 28130356

DOI: 10.1523/jneurosci.2068-16.2017

PubMed ID: 25533962

Title: Large-scale discovery of novel genetic causes of developmental disorders.

PubMed ID: 25533962

DOI: 10.1038/nature14135

PubMed ID: 29100089

Title: De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

PubMed ID: 29100089

DOI: 10.1016/j.ajhg.2017.10.003

PubMed ID: 29560374

Title: De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders.

PubMed ID: 29560374

DOI: 10.1002/acn3.528

PubMed ID: 29784083

Title: A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability.

PubMed ID: 29784083

DOI: 10.7554/elife.32451

PubMed ID: 35568036

Title: A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling.

PubMed ID: 35568036

DOI: 10.1016/j.cell.2022.04.028

Sequence Information:

  • Length: 478
  • Mass: 54088
  • Checksum: 208143A311BA9262
  • Sequence:
    • MATITCTRFT EEYQLFEELG KGAFSVVRRC VKVLAGQEYA AKIINTKKLS ARDHQKLERE 
ARICRLLKHP NIVRLHDSIS EEGHHYLIFD LVTGGELFED IVAREYYSEA DASHCIQQIL 
EAVLHCHQMG VVHRDLKPEN LLLASKLKGA AVKLADFGLA IEVEGEQQAW FGFAGTPGYL 
SPEVLRKDPY GKPVDLWACG VILYILLVGY PPFWDEDQHR LYQQIKAGAY DFPSPEWDTV 
TPEAKDLINK MLTINPSKRI TAAEALKHPW ISHRSTVASC MHRQETVDCL KKFNARRKLK 
GAILTTMLAT RNFSGGKSGG NKKSDGVKES SESTNTTIED EDTKVRKQEI IKVTEQLIEA 
ISNGDFESYT KMCDPGMTAF EPEALGNLVE GLDFHRFYFE NLWSRNSKPV HTTILNPHIH 
LMGDESACIA YIRITQYLDA GGIPRTAQSE ETRVWHRRDG KWQIVHFHRS GAPSVLPH

Genular Protein ID: 67767485

Symbol: Q8IWE0_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q8IWE0

Database IDs:

ARBA 7 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 ChEBI 11 ChiTaRS 1 DNASU 1 DisGeNET 1 EC 2 EMBL 2 GO 4 Gene3D 3 InterPro 6 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PROSITE 4 PROSITE-ProRule 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 RefSeq 2 Rhea 6 RuleBase 1 SAM 1 SMART 1 SUPFAM 2

Citations:

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

Sequence Information:

  • Length: 478
  • Mass: 54088
  • Checksum: BAE143AA03BA9264
  • Sequence:
    • MATITCTRFT EEYQLFEELG KGAFSVVRRC VKVLAGQEYA AKIINTKKLS ARDHQKLERE 
ARICRLLKHP NIVRLHDSIS EEGHHYLIFD LVTGGELFED IVAREYYSEA DASHCIQQIL 
EAVLHCHQMG VVHRDLKPEN LLLASKLKGA AVKLADFGLA IEVEGEQQAW FGFAGTPGYL 
SPEVLRKDPY GKPVDLWACG VILYILLVGY PPFWDEDQHR LYKQIKAGAY DFPSPEWDTV 
TPEAKDLINK MLTINPSKRI TAAEALKHPW ISHRSTVASC MHRQETVDCL KKFNARRKLK 
GAILTTMLAT RNFSGGKSGG NKKSDGVKES SESTNTTIED EDTKVRKQEI IKVTEQLIEA 
ISNGDFESYT KMCDPGMTAF EPEALGNLVE GLDFHRFYFE NLWSRNSKPV HTTILNPHIH 
LMGDESACIA YIRITQYLDA GGIPRTAQSE ETRVWHRRDG KWQIVHFHRS GAPSVLPH

Genular Protein ID: 2861623886

Symbol: A8K161_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K161

Database IDs:

ARBA 7 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CDD 1 CTD 1 ChEBI 11 ChiTaRS 1 DNASU 1 DisGeNET 1 EC 2 EMBL 4 ExpressionAtlas 1 GO 4 Gene3D 3 InterPro 6 KEGG 1 NCBI Taxonomy 1 OMA 1 OrthoDB 1 PANTHER 2 PROSITE 4 PROSITE-ProRule 1 Pfam 2 PharmGKB 1 RefSeq 2 Rhea 6 RuleBase 1 SAM 1 SMART 1 SMR 1 SUPFAM 2 VEuPathDB 1 iPTMnet 1

Citations:

PubMed ID: 11181995

Title: The sequence of the human genome.

PubMed ID: 11181995

DOI: 10.1126/science.1058040

Sequence Information:

  • Length: 489
  • Mass: 55320
  • Checksum: 41E67A1E15EB142B
  • Sequence:
    • MATITCTRFT EEYQLFEELG KGAFSVVRRC VKVLAGQEYA AKIINTKKLS ARDHQKLERE 
ARICRLLKHP NIVRLHDSIS EEGHHYLIFD LVTGGELFED IVAREYYSEA DASHCIQQIL 
EAVLHCHQMG VVHRDLKPEN LLLASKLKGA AVKLADFGLA IEVEGEQQAW FGFAGTPGYL 
SPEVLRKDPY GKPVDLWACG VILYILLVGY PPFWDEDQHR LYQQIKAGAY DFPSPEWDTV 
TPEAKDLINK MLTINPSKRI TAAEALKHPW ISHRSTVASC MHRQETVDCL KKFNARRKLK 
GAILTTMLAT RNFSGGKSGG NKKSDGVKKR KSSSSVQLME SSESTNTTIE DEDTKVRKQE 
IIKVTEQLIE AISNGDFESY TKMCDPGMTA FEPEALGNLV EGLDFHRFYF ENLWSRNSKP 
VHTTILNPHI HLMGDESACI AYIRITQYLD AGGIPRTAQS EETRVWHRRD GKWQIVHFHR 
SGAPSVLPH