RESUMO
Transient receptor potential canonical 3 (TRPC3) is a calcium-permeable, non-selective cation channel known to be regulated by components of the phospholipase C (PLC)-mediated signaling pathway, such as Ca2+, diacylglycerol (DAG) and phosphatidylinositol 4,5-biphosphate (PI(4,5)P2). However, the molecular gating mechanism by these regulators is not yet fully understood, especially its regulation by PI(4,5)P2, despite the importance of this channel in cardiovascular pathophysiology. Recently, Clarke et al. (2024) have reported that PI(4,5)P2 is a positive modulator for TRPC3 using molecular dynamics simulations and patch-clamp techniques. They have demonstrated a multistep gating mechanism of TRPC3 with the binding of PI(4,5)P2 to the lipid binding site located at the pre-S1/S1 nexus, and the propagation of PI(4,5)P2 sensing to the pore domain via a salt bridge between the TRP helix and the S4-S5 linker.
RESUMO
Achieving long-lasting neuronal modulation with low-intensity, low-frequency ultrasound is challenging. Here, we devised theta burst ultrasound stimulation (TBUS) with gamma bursts for brain entrainment and modulation of neuronal plasticity in the mouse motor cortex. We demonstrate that two types of TBUS, intermittent and continuous TBUS, induce bidirectional long-term potentiation or depression-like plasticity, respectively, as evidenced by changes in motor-evoked potentials. These effects depended on molecular pathways associated with long-term plasticity, including N-methyl-d-aspartate receptor and brain-derived neurotrophic factor/tropomyosin receptor kinase B activation, as well as de novo protein synthesis. Notably, bestrophin-1 and transient receptor potential ankyrin 1 play important roles in these enduring effects. Moreover, pretraining TBUS enhances the acquisition of previously unidentified motor skills. Our study unveils a promising protocol for ultrasound neuromodulation, enabling noninvasive and sustained modulation of brain function.