The magnesium, zinc and calcium ion channel TRPM7 is a channel-enzyme that has been implicated in synaptic and cognitive functions in the mammalian brain. How TRPM7 translates neuronal activity into activation of signaling pathways to regulate such functions remains largely unknown. Here, we found that calpain1 cleaves TRPM7 in neuronal activity-/calcium-dependent way, to release a C-terminal fragment containing the magnesium-dependent kinase domain (M7CK). Spatial proteomics, biochemical, cellular, transcriptomic and protein expression studies revealed that M7CK is translocated to nucleus to activate MEF2C to regulate expression of genes such as Prickle2 (a zinc binding protein) to regulate synapse density. Meanwhile, M7CK is translocated to dendrites to activate targets such as the mTOR-signaling member RPS6 to regulate synthesis of proteins including zinc transporter1 to control synaptic plasticity. Results provide insights of how TRPM7 activates distinct signaling pathways regulating distinct cellular functions necessary for supporting synaptic and cognitive functions in cell compartment-specific manner.