Affinage

CACNG4

Voltage-dependent calcium channel gamma-4 subunit · UniProt Q9UBN1

Length
327 aa
Mass
36.6 kDa
Annotated
2026-06-09
32 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNG4 is a voltage-dependent calcium channel gamma subunit that modulates calcium influx and the downstream signaling driven by it, with roles spanning neuronal excitability, cellular differentiation, and tumor progression (PMID:10613843, PMID:32062352). It was identified as a member of the calcium channel gamma subunit gene family by synteny to CACNG1 and CACNG2 (PMID:10613843). In the nervous system it acts within the corticothalamic circuit to suppress seizures, functioning redundantly with CACNG2: Cacng4 knockout mice are phenotypically normal, but combining the null allele with stargazer (Cacng2) mutations induces or worsens absence seizures (PMID:15677329). CACNG4 maintains the differentiated state of pancreatic beta-cells, where its deletion blunts glucose-stimulated insulin secretion and reduces the transcription factor MafA through a CaMKII-dependent pathway (PMID:35453520). In cancer, CACNG4 promotes breast cancer metastasis by closing the channel pore to limit calcium influx and reroute survival and metastatic signaling through effectors including AKT2, HDAC3, RASA1, and PKCζ (PMID:32062352), participates in a CUEDC1/CACNG4/PI3K axis that drives glycolysis and tumor growth in ER-positive breast cancer (PMID:41315933), and sustains hepatocellular carcinoma cancer stem cells (PMID:37909988).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 Medium

    Established CACNG4 as a distinct gene within the calcium channel gamma subunit family, placing it in a defined molecular context.

    Evidence Low-stringency genomic sequence analysis and synteny mapping against CACNG1/CACNG2

    PMID:10613843

    Open questions at the time
    • No functional or biochemical characterization of the encoded protein
    • Channel-modulating activity not yet demonstrated
  2. 2002 Medium

    Linked CACNG4 expression to the onset of cellular differentiation, raising the possibility it modulates calcium channels during development.

    Evidence In situ hybridization and developmental expression analysis in chick embryo neurons and myoblasts

    PMID:11884034

    Open questions at the time
    • Correlative expression only, no loss-of-function test
    • Direct channel target not identified
  3. 2005 High

    Defined an in vivo neuronal role by showing CACNG4 suppresses seizures redundantly with CACNG2 in the corticothalamic loop.

    Evidence Cacng4 knockout mouse with genetic epistasis against multiple stargazer (Cacng2) alleles, seizure phenotyping, expression localization

    PMID:15677329

    Open questions at the time
    • Specific channels regulated in thalamus not identified
    • Molecular basis of overlap with CACNG2 unresolved
  4. 2020 High

    Demonstrated that CACNG4 drives breast cancer metastasis by inhibiting calcium influx and rewiring survival/metastatic signaling.

    Evidence Gain/loss-of-function in 2D/3D culture, calcium influx assays, chick-CAM and mouse metastasis models, downstream effector profiling (AKT2/HDAC3/RASA1/PKCζ)

    PMID:32062352

    Open questions at the time
    • Direct physical link between CACNG4 and each effector not established
    • Channel pore-closing mechanism inferred pharmacologically
  5. 2022 High

    Showed CACNG4 maintains pancreatic beta-cell identity via a CaMKII→MafA pathway, extending its role to endocrine homeostasis.

    Evidence Cacng4 knockout mouse metabolic phenotyping, mRNA/protein analysis, CaMKII pathway dissection, validation in human islets and INS-1 cells

    PMID:35453520

    Open questions at the time
    • How CACNG4-modulated calcium signal activates CaMKII not detailed
    • Channel partner subunits in beta-cells unidentified
  6. 2023 Medium

    Implicated CACNG4 in maintaining the cancer stem cell state in hepatocellular carcinoma.

    Evidence ALDH1A1-high cell sorting, microarray, tumorsphere assays, amlodipine inhibition cytotoxicity

    PMID:37909988

    Open questions at the time
    • Amlodipine is not CACNG4-specific
    • Downstream signaling in CSCs not defined
  7. 2025 Medium

    Positioned CACNG4 within a CUEDC1/CACNG4/PI3K axis controlling glycolysis in ER-positive breast cancer.

    Evidence RNA-seq, ChIP, dual-luciferase reporter, glycolysis assays, xenograft model

    PMID:41315933

    Open questions at the time
    • Mechanism by which CUEDC1 modulates CACNG4 not biochemically resolved
    • Relationship to calcium influx in this context unclear
  8. 2026 Medium

    Identified CACNG4 suppression as a node downstream of exosomal miR-221-5p driving orbital fibroblast pathology in Graves' orbitopathy.

    Evidence Exosome characterization, primary fibroblast assays, miR-221-5p inhibition rescue, in vivo GO model, scRNA-seq

    PMID:42203012

    Open questions at the time
    • Direct miR-221-5p binding to CACNG4 transcript not detailed
    • Link between CACNG4 and AMPK signaling mechanistically thin

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CACNG4's channel-modulating activity is mechanistically coupled to the diverse downstream pathways (CaMKII, AKT2/PI3K, AMPK) across tissues remains unresolved.
  • No structural model of CACNG4-channel interaction in the timeline
  • Whether pore modulation is the common mechanism across all contexts is untested
  • Direct physical partners of CACNG4 not biochemically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Pathway
R-HSA-162582 Signal Transduction 2
Partners

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 CACNG4 was identified as a novel calcium channel gamma subunit gene located on chromosome 17, discovered through low-stringency genomic sequence analysis of regions syntenic to CACNG1 and CACNG2, establishing it as a member of the voltage-dependent Ca2+ channel gamma subunit gene family generated by tandem and chromosome duplication. Genomic sequence analysis, gene family identification by synteny Genome research Medium 10613843
2005 CACNG4 has seizure-suppressing activity in the corticothalamic circuit; homozygous Cacng4 knockout mice appear phenotypically normal, but combining the Cacng4 null allele with stargazer (Cacng2) mutant alleles exacerbates or induces absence seizures, demonstrating overlapping in vivo functions between CACNG4 and CACNG2 and restricting CACNG4 expression to the thalamus within the corticothalamic loop. Targeted gene disruption (knockout mouse), genetic epistasis (double mutant with Cacng2 alleles), seizure phenotype analysis, expression analysis Proceedings of the National Academy of Sciences of the United States of America High 15677329
2002 Chick CACNG4 is expressed in differentiating neurons and myoblasts during early development, with expression timing correlating precisely with the onset of neuronal differentiation in cranial and dorsal root ganglia and in the myotome, suggesting a role in modulating calcium channels during cellular differentiation. In situ hybridization, developmental expression analysis in chick embryo Developmental biology Medium 11884034
2020 CACNG4 promotes breast cancer metastasis by closing the channel pore to inhibit calcium influx, thereby altering calcium signaling through key survival and metastatic pathway genes including AKT2, HDAC3, RASA1, and PKCζ; CACNG4 overexpression alters cell motility in vitro, induces malignant transformation in 3D culture, and increases lung-specific metastasis in vivo. In vitro 2D and 3D assays, intracellular calcium influx assays, chick-CAM model, mouse metastasis model, gain/loss-of-function experiments, calcium channel blocker treatment EBioMedicine High 32062352
2022 CACNG4 (CaVγ4) is required for pancreatic beta-cell maintenance of its differentiated state; Cacng4 knockout mice exhibit impaired fasting glucose and impaired glucose tolerance with blunted glucose-stimulated insulin secretion. CaVγ4 deletion reduces expression of the transcription factor MafA (on mRNA and protein levels), and CaMKII mediates the regulatory pathway linking CaVγ4 to MafA, as confirmed in mouse islets, human donor islets, and INS-1 832/13 cells. Cacng4 knockout mouse (in vivo glucose tolerance and insulin secretion assays), gene expression analysis (mRNA and protein), CaMKII pathway investigation, human islet RNA-seq validation, INS-1 cell line experiments Biomedicines High 35453520
2025 CUEDC1 directly modulates CACNG4 to enhance PI3K/AKT pathway activation, thereby facilitating glycolysis (via GLUT1 upregulation) and tumor growth in ER-positive breast cancer; this CUEDC1/CACNG4/PI3K axis was identified by RNA-seq, ChIP, and dual-luciferase reporter assays, with MAZ transcription factor upregulating CUEDC1 transcription. Dual-luciferase reporter assay, RNA-seq, chromatin immunoprecipitation (ChIP), metabolic glycolysis assays, mouse xenograft model, western blotting, qRT-PCR Cellular & molecular biology letters Medium 41315933
2023 CACNG4 is upregulated in cancer stem cells (CSCs) of hepatocellular carcinoma (HCC); pharmacological inhibition of CACNG4 with amlodipine at low concentrations preferentially reduced CSC viability, markedly decreased tumorsphere formation, and reduced the ALDH1A1-high cell population, indicating a role for CACNG4 in maintaining the CSC state. FACS sorting of ALDH1A1-high cells, microarray gene expression analysis, tumorsphere formation assay, cytotoxicity assay with amlodipine (CACNG4 inhibitor) Anticancer research Medium 37909988
2026 In Graves' orbitopathy, exosomal miR-221-5p suppresses CACNG4/AMPK signaling in orbital fibroblasts, driving proinflammatory, profibrotic, and adipogenic phenotypes; partial rescue of these pathogenic phenotypes by miR-221-5p inhibition confirmed the functional centrality of CACNG4 suppression in this pathway. Exosome isolation and characterization, primary human orbital fibroblast functional assays, miR-221-5p inhibition, in vivo mouse GO model, single-cell RNA sequencing, histopathology, MRI Experimental eye research Medium 42203012

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Identification of three novel Ca(2+) channel gamma subunit genes reveals molecular diversification by tandem and chromosome duplication. Genome research 55 10613843
2016 Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia. Scientific reports 54 27102562
2009 Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib. Laboratory investigation. Journal of neurosurgery 44 19301967
2020 Amplification of a calcium channel subunit CACNG4 increases breast cancer metastasis. EBioMedicine 34 32062352
2005 A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice. Proceedings of the National Academy of Sciences of the United States of America 30 15677329
2016 Single-cell analyses of transcriptional heterogeneity in squamous cell carcinoma of urinary bladder. Oncotarget 25 27602771
2002 Identification and characterization of a calcium channel gamma subunit expressed in differentiating neurons and myoblasts. Developmental biology 23 11884034
2016 Different Profile of mRNA Expression in Sinoatrial Node from Streptozotocin-Induced Diabetic Rat. PloS one 22 27096430
2021 Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder. Molecular psychiatry 21 34349225
2018 The Pattern of mRNA Expression Is Changed in Sinoatrial Node from Goto-Kakizaki Type 2 Diabetic Rat Heart. Journal of diabetes research 20 30246030
2022 Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer. Frontiers in immunology 18 36569910
2007 [Novel methylation and expression markers associated with breast cancer]. Molekuliarnaia biologiia 17 17936981
2020 Novel genes involved in the genetic architecture of temperament in Brahman cattle. PloS one 16 32822435
2016 Identification of Transcription Factor-Gene Regulatory Network in Acute Myocardial Infarction. Heart, lung & circulation 16 27746059
2021 Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Cervical Intraepithelial Neoplasia in Chinese Women Living With HIV. Frontiers in cellular and infection microbiology 15 34557425
2018 Identify Down syndrome transcriptome associations using integrative analysis of microarray database and correlation-interaction network. Human genomics 15 29351810
2018 Dominance effects of ion transport and ion transport regulator genes on the final weight and backfat thickness of Landrace pigs by dominance deviation analysis. Genes & genomics 13 30136073
2021 Transcriptome study of oleanolic acid in the inhibition of breast tumor growth based on high-throughput sequencing. Aging 12 34607975
2013 Transforming growth factor-β1 primes proliferating adult neural progenitor cells to electrophysiological functionality. Glia 9 24038377
2019 Exploring the molecular basis of neuronal excitability in a vocal learner. BMC genomics 8 31375088
2007 Quantitative trait locus that determines the cross-sectional shape of the femur in SAMP6 and SAMP2 mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 7 17295603
2023 Cancer Stem Cells of Hepatocellular Carcinoma Are Suppressed by the Voltage-gated Calcium Channel Inhibitor Amlodipine. Anticancer research 5 37909988
2024 Rare and common variants associated with alcohol consumption identify a conserved molecular network. Alcohol, clinical & experimental research 4 39031522
2024 Multi-Omics Approach Reveals Genes and Pathways Affected in Miller-Dieker Syndrome. Molecular neurobiology 4 39508990
2022 The Calcium Channel Subunit Gamma-4 as a Novel Regulator of MafA in Pancreatic Beta-Cell Controls Glucose Homeostasis. Biomedicines 4 35453520
2023 Transcriptomic profiles of the ruminal wall in Italian Mediterranean dairy buffaloes fed green forage. BMC genomics 2 36941576
2025 CUEDC1 promotes glycolytic metabolism reprogramming through the CUEDC1/CACNG4/PI3K axis to promote ER-positive breast cancer growth. Cellular & molecular biology letters 1 41315933
2024 Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network. bioRxiv : the preprint server for biology 1 38464225
2023 Genetic Variants and Their Putative Effects on microRNA-Seed Sites: Characterization of the 3' Untranslated Region of Genes Associated with Temperament. Genes 1 37239364
2023 Identification and validation of molecular subtypes and a 9-gene risk model for breast cancer. Medicine 1 37747033
2026 Plasma-derived exosomes from Graves' orbitopathy: Pathogenic entities causing tissue lesions. Experimental eye research 0 42203012
2024 Identification of diagnostic biomarkers in prostate cancer-related fatigue by construction of predictive models and experimental validation. British journal of cancer 0 39676131

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