PKC-gamma calcium signaling 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].

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