TRPM7 is critical for short-term synaptic depression by regulating synaptic vesicle endocytosis

Abstract

TRPM7 contributes to a variety of physiological and pathological processes in many tissues and cells. With a widespread distribution in the nervous system, TRPM7 is involved in animal behaviors and neuronal death induced by ischemia. However, the physiological role of TRPM7 in CNS neuron remains unclear. Here, we identify endocytic defects in neuroendocrine cells and neurons from TRPM7 knockout (KO) mice, indicating a role of TRPM7 in synaptic vesicle endocytosis. Our experiments further pinpoint the importance of TRPM7 as an ion channel in synaptic vesicle endocytosis. Ca2+ imaging detects a defect in presynaptic Ca2+ dynamics in TRPM7 KO neuron, suggesting an importance of Ca2+ influx via TRPM7 in synaptic vesicle endocytosis. Moreover, the short-term depression is enhanced in both excitatory and inhibitory synaptic transmission from TRPM7 KO mice. Taken together, our data suggests that Ca2+ influx via TRPM7 may be critical for short-term plasticity of synaptic strength by regulating synaptic vesicle endocytosis in neurons.

TRPM7 kinase activity induces amyloid-β degradation to reverse synaptic and cognitive deficits in mouse models of Alzheimer’s disease

“…In neuroblastoma cells, activation of TRPM7 channels increases basal autophagy and reduces Aβ levels ( 21 ). In vitro and in vivo studies show that deletion of TRPM7 and/or its kinase domain or suppression of its expression results in synaptic and cognitive dysfunctions ( 16 , 22 , 23 ). Synapse loss and memory deficits are among the major hallmarks of AD pathology ( 1 ).…”

“…Some studies suggest that overexpression or increased activation of TRPM7 contributes to the pathologies of neurodegenerative disorders and, hence, that its suppression or inhibition represents a therapeutic strategy (17). In contrast, various other studies show that mutations in TRPM7 are associated with the neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (18), that activation of TRPM7 decreases Aβ levels in cultured cell lines (19)(20)(21), and that TRPM7 or its kinase domain are critical for normal synaptic and cognitive functions (16,22,23). Thus, reductions in TRPM7 activity or expression could also contribute to pathologies of neurodegenerative disorders.…”

Ischemia-Reperfusion Increases TRPM7 Expression in Mouse Retinas

“…As a particular characteristic, only shared with its closely related family member TRPM6, TRPM7 contains both an ion channel and a serine-threonine kinase domain in its C-terminal portion, which have independent functions [31,34]. On the one hand, the movement of divalent cations across the ion channel can depolarize excitatory cells and cause intracellular calcium overload, with plenty of associated effects [35,36]. On the other hand, due to its kinase domain, TRPM7 can auto-phosphorylate or activate different substrates such as annexin-A1, myosin IIA or phospholipase Cγ2.…”

The Structural Basis of Long-Term Potentiation in Hippocampal Synapses, Revealed by Electron Microscopy Imaging of Lanthanum-Induced Synaptic Vesicle Recycling

“…This may someday be explained by several different mechanisms: for example, by some sort of “stiffening” of the presynaptic membrane or by La+++ tending to “glue” the presynaptic membrane to the extracellular matrix, or possibly by blocking sodium and calcium entry through the presynaptic membrane, which may in some way directly slow down some aspect of the recycling process. Indeed, there is a large body of evidence, which suggests that clathrin-coated vesicle formation and/or synaptic vesicle recycling is somehow dependent on intracellular Ca ++ being at just the right level ( Henkel and Betz, 1995 ; Neale et al, 1999 ; Vogel et al, 1999 ; Teng and Wilkinson, 2003 ; Zefirov et al, 2006 ; Yao et al, 2009 ; Morton et al, 2015 ; Miyano et al, 2019 ; Bourgeois-Jaarsma et al, 2021 ; Jiang et al, 2021 ). In any case, it is abundantly clear from the present observations and from the past work that lanthanum somehow creates a greater imbalance between exocytosis and endocytosis than any other form of synaptic stimulation, and consequently, produces the most enhanced accumulation of synaptic vesicle membrane on the presynaptic surface, and thus, the greatest expansion of the presynaptic membrane.…”