Neuroprotective intracellular signaling pathways in the central nervous system involving TRPC6 activation

Neuroprotective intracellular signaling pathways in the central nervous system involving TRPC6 activation. A detailed description of pathways is given in the 3rd, 4th and 5th sections. Presumably, TRPC6 may impede the extrasynaptic NR2B-containing NMDAR-dependent calcium influx via calcineurin-involving dephosphorylation mechanism (see the dashed lines). On the other hand, activation of synaptic NR2A-containing NMDAR may increase TRPC6 mRNA synthesis through a calcineurin/nuclear factor of activated T-cells-dependent pathway in cortical neurons (see the solid lines). Agonism of synaptic NMDAR has been proposed to underlie the activation of synaptoprotective store-operated calcium entry via TRPC6 in hippocampal silent synapses. TPRC6 is key component of store-operated calcium entry in hippocampal neurons. TRPC6 may be activated directly either by DAG or pharmacological agent such as hyperforin as well as by store-depletion (following IP3R activation). Upon store depletion of ER, the STIM2 detects calcium level reduction and activates Orai2/TRPC6 channels complex. Calcium entry via TRPC6-neuronal SOCE is needed to activate CaMKII, which can phosphorylate AMPAR. This promotes AMPARs trafficking to the post-synaptic membrane, which increases membrane depolarization and enhances NMDAR’s contribution to LTP maintenance. In addition, in neuronal tumor cells TRPC6-induced calcium entry is essential for the biosynthesis of endocannabinoids (2-AG, AEA) that have anti-inflammatory properties. Supposedly, neuroprotective effects are achieved by suppressing NF-κB via activation of the PPARγ. The binding of BDNF to TrkB results in the PLC-dependent activation of TRPC6. Calcium influx through TRPC6 may also activate CREB through three signal cascades: Ras/MEK/ERK, RAS/PI3K/Akt, and CaM/CAMKIV. Neuroprotective effect is achieved via CREB-dependent activation of the BDNF transcription. Moreover, in DGC and GABAergic interneurons TRPC6 may impact on Kv4.3 translocation to the neuronal membrane via ERK-dependent signaling (indicated by a wavy line). Kv4.3 impedes fast-spiking in interneurons, and afterwards increases neuronal excitability in principal neurons. Thus, TRPC6 possibly plays a role in regulation of neuronal excitability. Finally, TRPC6-ERK1/2 neuroprotective signaling pathway has been also reported to protect DGC via facilitation of mitochondrial fission (indicated by a wavy line).

Publication

Role of Neuronal TRPC6 Channels in Synapse Development, Memory Formation and Animal Behavior (2023) Nikita Zernov, et al. Int J Mol Sci. 2023 Oct;24(20). Figure: F1. Homo sapiens

Disease mentions