Aslam Naveed, Alvi Farah
BioSystOmics, Houston, TX, United States.
Department of Physics, COMSATS University Islamabad, Lahore Campus, Pakistan.
Front Mol Biosci. 2022 Feb 21;9:818682. doi: 10.3389/fmolb.2022.818682. eCollection 2022.
Canonical transient receptor potential channels (TRPC3) may play a pivotal role in the development and viability of dendritic arbor in Purkinje neurons. This is a novel postsynaptic channel for glutamatergic synaptic transmission. In the cerebellum, TRPC3 appears to regulate functions relating to motor coordination in a highly specific manner. Gain of TRPC3 function is linked to significant alterations in the density and connectivity of dendritic arbor in Purkinje neurons. TRPC3 signals downstream of class I metabotropic glutamate receptors (mGluR1). Moreover, diacylglycerol (DAG) can directly bind and activate TRPC3 molecules. Here, we investigate a key question: How can the activity of the TRPC3 channel be regulated in Purkinje neurons? We also explore how mGluR1 activation, Ca influx, and DAG homeostasis in Purkinje neurons can be linked to TRPC3 activity modulation. Through systems biology approach, we show that TRPC3 activity can be modulated by a Purkinje cell (PC)-specific local signalosome. The assembly of this signalosome is coordinated by DAG generation after mGluR1 activation. Our results also suggest that purinergic receptor activation leads to the spatial and temporal organization of the TRPC3 signaling module and integration of its key effector molecules such as DAG, PKC, DGK, and Ca into an organized local signalosome. This signaling machine can regulate the TRPC3 cycling between active, inactive, and desensitized states. Precise activity of the TRPC3 channel is essential for tightly regulating the Ca entry into PCs and thus the balance of lipid and Ca signaling in Purkinje neurons and hence their viability. Cell-type-specific understanding of mechanisms regulating TRPC3 channel activity could be key in identifying therapeutic targeting opportunities.
典型瞬时受体电位通道（TRPC3）可能在浦肯野神经元树突分支的发育和存活中起关键作用。这是一种用于谷氨酸能突触传递的新型突触后通道。在小脑中，TRPC3似乎以高度特异性的方式调节与运动协调相关的功能。TRPC3功能的增强与浦肯野神经元树突分支的密度和连接性的显著改变有关。TRPC3在I类代谢型谷氨酸受体（mGluR1）的下游发出信号。此外，二酰基甘油（DAG）可以直接结合并激活TRPC3分子。在此，我们研究一个关键问题：TRPC3通道的活性在浦肯野神经元中如何被调节？我们还探讨浦肯野神经元中的mGluR1激活、钙内流和DAG稳态如何与TRPC3活性调节相关联。通过系统生物学方法，我们表明TRPC3活性可由浦肯野细胞（PC）特异性局部信号体调节。该信号体的组装由mGluR1激活后DAG的产生协调。我们的结果还表明嘌呤能受体激活导致TRPC3信号模块的空间和时间组织，并将其关键效应分子如DAG、PKC、DGK和Ca整合到一个有组织的局部信号体中。这种信号机制可以调节TRPC3在活性、非活性和脱敏状态之间的循环。TRPC3通道的精确活性对于严格调节钙进入PCs至关重要，从而维持浦肯野神经元中脂质和钙信号的平衡以及它们的存活能力。对调节TRPC3通道活性机制的细胞类型特异性理解可能是确定治疗靶点机会的关键。
