Details for: PRKAG3

Gene ID: 53632

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: PRKAG3

Ensembl ID: ENSG00000115592

Description: protein kinase AMP-activated non-catalytic subunit gamma 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • glutamatergic neuron CL0000679
    CSI 7.87
    rCSI 16.18%
    PRS 99.7
  • GABAergic neuron CL0000617
    CSI 5.09
    rCSI 17.05%
    PRS 99.71

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 [PRKAG3](/details-gene/53632), or Protein Kinase AMP-activated Non-catalytic Subunit Gamma 3, encodes a regulatory gamma subunit of the 5'-AMP-activated protein kinase (AMPK) complex. AMPK is a master sensor of cellular energy status, playing a critical role in maintaining metabolic homeostasis. The primary function of the [PRKAG3](/details-gene/53632) subunit involves binding adenosine nucleotides (AMP, ADP, and ATP), which allosterically regulates AMPK activity in response to changes in the cellular energy charge [Link](https://doi.org/10.1042/bj3460659), [Link](https://doi.org/10.1172/jci19874). **Overall**, expression data indicate a highly specialized role for this isoform, with significant expression predominantly observed in neuronal cell types, particularly [glutamatergic neuron](/details-cell/CL0000679) and [GABAergic neuron](/details-cell/CL0000617), suggesting it is a key component of metabolic regulation in the central nervous system. ## Cellular Roles and Expression Landscape The expression profile of [PRKAG3](/details-gene/53632) points to a specialized function within the nervous system. The highest significance is observed in two major classes of neurons: [glutamatergic neuron](/details-cell/CL0000679) (CSI: 7.87) and [GABAergic neuron](/details-cell/CL0000617) (CSI: 5.09). This enrichment suggests that the [PRKAG3](/details-gene/53632) isoform of the AMPK complex is a crucial workhorse for managing the high and fluctuating energy demands associated with synaptic transmission and neuronal activity. While historically studied for its role in skeletal muscle glycogen metabolism, particularly in pig models [Link](https://doi.org/10.1126/science.288.5469.1248), these data highlight its prominent role in neuronal biology. The focused expression in these cell types suggests that its function is tailored to the specific metabolic challenges of the brain, rather than being a ubiquitous component of the AMPK complex across all tissues. ## Pathways and Molecular Function The functions of [PRKAG3](/details-gene/53632) are intrinsically linked to its role as a subunit of the AMPK complex, a central regulator of cellular metabolism [Link](https://doi.org/10.1038/nrm2249). Gene Ontology annotations underscore its involvement in fundamental metabolic processes, including `[Cellular response to glucose starvation](/details-pathway/GO:0042149)`, `[Negative regulation of glycogen biosynthetic process](/details-pathway/GO:0045719)`, and `[Regulation of glycolytic process](/details-pathway/GO:0006110)`. These functions are critical for cells with high energy turnover like neurons. Consistent with its high expression in neuronal populations, [PRKAG3](/details-gene/53632) is implicated in numerous Reactome pathways related to neuronal function and signaling. These include `[Transmission across chemical synapses](/details-pathway/R-HSA-112315)` and `[Activation of nmda receptors and postsynaptic events](/details-pathway/R-HSA-442755)`. This suggests that the [PRKAG3](/details-gene/53632)-containing AMPK complex may couple synaptic activity to local energy regulation. Furthermore, its role in pathways like `[Translocation of slc2a4 (glut4) to the plasma membrane](/details-pathway/R-HSA-1445148)` and `[Autophagy](/details-pathway/R-HSA-9612973)` indicates that it helps neurons adapt to metabolic stress by modulating glucose uptake and cellular recycling processes. The gene's involvement in `[Mtor signalling](/details-pathway/R-HSA-165159)` further positions it at the intersection of nutrient sensing, cell growth, and catabolic processes. ## Research Directions The specific enrichment of [PRKAG3](/details-gene/53632) in glutamatergic and GABAergic neurons, coupled with its role in fundamental energy sensing, presents several avenues for future investigation, particularly concerning neuro-metabolic coupling and disease. **Proposed Hypotheses:** 1. [PRKAG3](/details-gene/53632) is a critical mediator of neuronal survival during excitotoxicity. Its function is required to restore metabolic homeostasis following excessive NMDA receptor activation, and its dysfunction could exacerbate neuronal damage in ischemic events or neurodegenerative conditions. 2. The [PRKAG3](/details-gene/53632) isoform confers specific regulatory properties to the AMPK complex that are essential for activity-dependent plasticity. It may be required for coupling sustained synaptic firing with mitochondrial biogenesis and local glucose uptake at synapses, thereby supporting long-term potentiation (LTP). **Experimental Approach:** To test the second hypothesis, a conditional knockout of [PRKAG3](/details-gene/53632) in glutamatergic neurons of the hippocampus could be generated in mice. Electrophysiological recordings from hippocampal slices could then be used to assess whether the induction and maintenance of LTP are impaired in the absence of [PRKAG3](/details-gene/53632). This could be complemented with molecular analyses, such as measuring the phosphorylation status of AMPK targets and assessing GLUT4 translocation to the neuronal membrane in response to synaptic stimulation. Furthermore, live-cell imaging using fluorescent glucose sensors in cultured knockout neurons could directly visualize defects in activity-dependent glucose uptake. **Therapeutic Potential:** As an intracellular regulatory protein, [PRKAG3](/details-gene/53632) itself is not a conventional drug target. However, pharmacological activation of the AMPK complex is a well-established therapeutic strategy for metabolic disorders. Given its neuron-specific expression profile, developing isoform-specific activators that target the [PRKAG3](/details-gene/53632)-containing AMPK complex could represent a novel therapeutic avenue for neurodegenerative diseases characterized by metabolic deficits, such as Alzheimer's or Parkinson's disease. Such a strategy would aim for **activation** of the complex to enhance neuronal energy production and stress resistance, potentially offering a more targeted intervention with fewer systemic side effects than pan-AMPK activators.

Genular Protein ID: 4241132382

Symbol: AAKG3_HUMAN

Name: 5'-AMP-activated protein kinase subunit gamma-3

UniProtKB Accession Codes:

Q9UGI9 Q4QQG8 Q4V779 Q9NRL1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CORUM 1 CTD 1 ChEBI 35 ChEMBL 4 ComplexPortal 4 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 EMBL 6 Ensembl 2 ExpressionAtlas 1 GO 17 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 2 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 8 RefSeq 2 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 10698692

Title: Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding.

PubMed ID: 10698692

DOI: 10.1042/bj3460659

PubMed ID: 10818001

Title: A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle.

PubMed ID: 10818001

DOI: 10.1126/science.288.5469.1248

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

PubMed ID: 14722619

Title: CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations.

PubMed ID: 14722619

DOI: 10.1172/jci19874

PubMed ID: 17255938

Title: Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit.

PubMed ID: 17255938

DOI: 10.1038/sj.emboj.7601542

PubMed ID: 17307971

Title: AMP-activated protein kinase in metabolic control and insulin signaling.

PubMed ID: 17307971

DOI: 10.1161/01.res.0000256090.42690.05

PubMed ID: 17712357

Title: AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.

PubMed ID: 17712357

DOI: 10.1038/nrm2249

PubMed ID: 21460634

Title: Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop.

PubMed ID: 21460634

DOI: 10.4161/auto.7.7.15451

PubMed ID: 24563466

Title: Cross-talk between two essential nutrient-sensitive enzymes: O-GlcNAc transferase (OGT) and AMP-activated protein kinase (AMPK).

PubMed ID: 24563466

DOI: 10.1074/jbc.m113.523068

PubMed ID: 17878938

Title: Gain-of-function R225W mutation in human AMPKgamma(3) causing increased glycogen and decreased triglyceride in skeletal muscle.

PubMed ID: 17878938

DOI: 10.1371/journal.pone.0000903

Sequence Information:

  • Length: 489
  • Mass: 54258
  • Checksum: 0E93E2B5117B328D
  • Sequence:
    • MEPGLEHALR RTPSWSSLGG SEHQEMSFLE QENSSSWPSP AVTSSSERIR GKRRAKALRW 
TRQKSVEEGE PPGQGEGPRS RPAAESTGLE ATFPKTTPLA QADPAGVGTP PTGWDCLPSD 
CTASAAGSST DDVELATEFP ATEAWECELE GLLEERPALC LSPQAPFPKL GWDDELRKPG 
AQIYMRFMQE HTCYDAMATS SKLVIFDTML EIKKAFFALV ANGVRAAPLW DSKKQSFVGM 
LTITDFILVL HRYYRSPLVQ IYEIEQHKIE TWREIYLQGC FKPLVSISPN DSLFEAVYTL 
IKNRIHRLPV LDPVSGNVLH ILTHKRLLKF LHIFGSLLPR PSFLYRTIQD LGIGTFRDLA 
VVLETAPILT ALDIFVDRRV SALPVVNECG QVVGLYSRFD VIHLAAQQTY NHLDMSVGEA 
LRQRTLCLEG VLSCQPHESL GEVIDRIARE QVHRLVLVDE TQHLLGVVSL SDILQALVLS 
PAGIDALGA