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Based on the information gathered, let me now provide a comprehensive review of the GO-CAM model gomodel:65f3ae5c00002132 "Control of GABAAR clustering to GABAergic synapses by Gephyrin (Human)".

Review of GO-CAM model: gomodel:65f3ae5c00002132

Overview

This GO-CAM model focuses on the control of GABAA receptor (GABAAR) clustering at GABAergic synapses by Gephyrin in human neurons. The model depicts several activities:

  1. GABA-A receptor activities performed by various GABAAR subunits (GABRG2, GABRB3, GABRA1, GABRB2)
  2. Protein-macromolecule adaptor activity of Gephyrin (GPHN) in clustering GABAA receptors
  3. Protein-cysteine S-palmitoyltransferase activity of ZDHHC12 in palmitoylating Gephyrin

Model Strengths

  1. Biological accuracy: The model correctly represents the key roles of Gephyrin as a scaffold protein that clusters GABAA receptors at inhibitory synapses, which is well supported by literature (PMID:25025157).

  2. Causal relationships: The model properly depicts the causal relationship between ZDHHC12's palmitoyltransferase activity and Gephyrin's adaptor function, which is crucial for GABAAR clustering as demonstrated in the literature.

  3. Molecular detail: The model includes specific GABAAR subunits (GABRG2, GABRB3, GABRA1, GABRB2) that are known to interact with Gephyrin at inhibitory synapses.

  4. Evidence quality: The model uses direct experimental evidence (ECO:0000314, ECO:0000315) from peer-reviewed publications to support the relationships.

  5. Subcellular localization: The model correctly annotates the activities as occurring in the postsynaptic membrane (GO:0045211), which is appropriate for this pathway.

Areas for Improvement

  1. Missing GABAAR complex representation: The model represents individual GABAAR subunits carrying the GABA-A receptor activity (GO:0004890), but GABAARs function as heteropentameric complexes. According to the "How to annotate complexes in GO-CAM" document, when the activity is shared by several proteins that form a complex (like in heteromeric receptors), it would be more appropriate to represent this functional relationship.

  2. Redundant causal relationships: There appear to be duplicate causal associations from GPHN to several GABAAR subunits. For example, there are two identical causal relationships from GPHN to GABRG2 with the same predicate (RO:0002629) and evidence. This is redundant and should be corrected.

  3. Input/output relationships clarity: All GABAAR activities have CHEBI:17996 (chloride) as both input and output, which is appropriate for a chloride channel, but the model could benefit from including GABA (CHEBI:16865) as an input to better represent the receptor's activation mechanism.

  4. Additional molecular players: Based on PMID:25025157, Gephyrin requires palmitoylation on two specific cysteine residues (Cys212 and Cys284) to properly cluster at GABAergic synapses. The model could be enriched by including this molecular detail.

  5. Activity flow representation: While the model correctly shows that ZDHHC12 palmitoylates Gephyrin, which then clusters GABAARs, the biological process context for each activity could be more clearly defined to show the complete pathway for GABAAR trafficking and clustering.

Specific Recommendations

  1. Improve GABAAR representation: Consider representing the GABAAR as a complex using the GO term for "GABA-A receptor complex" (GO:1902711) for activities where the specific subunit carrying the activity is not definitively known.

  2. Remove redundant causal associations: Clean up the duplicate causal relationships from GPHN to GABAAR subunits.

  3. Enhance molecular detail: Add annotations to indicate the specific palmitoylation sites (Cys212 and Cys284) on Gephyrin that are modified by ZDHHC12.

  4. Complete pathway context: Include annotations for the broader biological processes of "inhibitory synapse assembly" (GO:0097091) and "GABA signaling pathway" (GO:0007214) to provide better context for the activities.

  5. Strengthen evidence: Consider adding evidence from additional publications to support the role of Gephyrin in clustering specific GABAAR subunits.

Conclusion

GO-CAM model gomodel:65f3ae5c00002132 provides a good representation of the molecular mechanism by which Gephyrin, when palmitoylated by ZDHHC12, clusters GABAA receptors at inhibitory synapses. This is an important process for maintaining proper inhibitory neurotransmission in the human brain. The model is generally well-constructed and evidence-based but could benefit from a few refinements to better represent the complexities of GABAAR function and provide a more complete picture of the pathway.

The model correctly captures the key finding from PMID:25025157 that palmitoylation of Gephyrin by ZDHHC12 is essential for proper clustering of GABAARs at inhibitory synapses. Overall, this is a valuable contribution to understanding the molecular mechanisms of inhibitory synapse formation and function.