PKC-gamma calcium signaling pathway in ataxia (WP4760)

PKC-gamma calcium-signaling pathway in Ataxia. Upon ligand binding, the mGluR1 receptor is followed by activation of Gq causing PLC-mediated hydrolysis of PIP2 into IP3 and DAG. Binding of IP3 to the IP3R1 induces Ca2+ release from the endoplasmic reticulum to the cytoplasm. This step is controlled by CAR8, which can inhibit binding of IP3 to the IP3R1. Simultaneous binding of Ca2+ to PKC-gamma C2 domain and of DAG to the C1 domain of PKC-gamma induce translocation of PKC-gamma to the plasma membrane. There, the pseudosubstrate is released from the kinase domain, allowing phosphorylation of downstream target proteins, including GRIA1. PKC exerts an inhibitory effect on TRPC3 channel either directly through phosphorylation or indirectly. A rise of the intracellular calcium concentration can also be mediated by the voltage-gated Ca2+ channel Cav2.1 or TRPC3. Conversely, PMCA2 can efficiently remove Ca2+ from the cytoplasm. Mutations: * mGluR1 - Ataxia * CA8: Ataxia * IP3R1: spinocerebellar ataxia type 1,2,3 / 15,16 / 29 * PRKCG: spinocerebellar ataxia type 14 * CACNA1A: spinocerebellar ataxia type 6 * TRPC3: spinocerebellar ataxia type 41 * ATP2B2: Ataxia This pathway is based on fig 1B from [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883377/ Shimobayashi and Kapfhammer].
last edited

Authors

Khanspers and Egonw

Cited In

Organism

Homo sapiens

Communities

Diseases

Annotations

Pathway Ontology: altered calcium homeostasis pathway

Disease Ontology: neurodegenerative disease hereditary ataxia

Participants

Label Type Compact Identifier
GRIA2 GeneProduct ensembl:ENSG00000120251
Na+ Metabolite chebi:29101
HOMER3 GeneProduct ensembl:ENSG00000051128
RYR3 GeneProduct ensembl:ENSG00000198838
IP3 Metabolite hmdb:HMDB0001498
PI(3,4,5)P3 Metabolite wikidata:Q3078767
TRPC3 GeneProduct ensembl:ENSG00000138741
Ca2+ Metabolite chebi:29108
GNAQ GeneProduct ensembl:ENSG00000156052
GRM1 GeneProduct ensembl:ENSG00000152822
GRIA1 GeneProduct ensembl:ENSG00000155511
CACNA1A GeneProduct ensembl:ENSG00000141837
IP3R1 GeneProduct ensembl:ENSG00000150995
DAG Metabolite chebi:18035
PLCB1 GeneProduct ensembl:ENSG00000182621
CA8 GeneProduct ensembl:ENSG00000178538
PRKCG GeneProduct ensembl:ENSG00000126583
PIP2 Metabolite wikidata:Q3083814
PDK1 GeneProduct ensembl:ENSG00000152256
PLCB2 GeneProduct ensembl:ENSG00000137841
PLCB3 GeneProduct ensembl:ENSG00000149782
PLCB4 GeneProduct ensembl:ENSG00000101333
GNA11 GeneProduct ensembl:ENSG00000088256
GNA14 GeneProduct ensembl:ENSG00000156049
GNA15 GeneProduct ensembl:ENSG00000060558
GRIA3 GeneProduct ensembl:ENSG00000125675
GRIA4 GeneProduct ensembl:ENSG00000152578
ATP2B2 GeneProduct ensembl:ENSG00000157087
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Ca2+ Metabolite chebi:29108
Na+ Metabolite chebi:29101

References

  1. Shimobayashi E, Kapfhammer JP. Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development. Curr Neuropharmacol. 2018 Jan 30;16(2):151–9. PubMed Europe PMC Scholia