Isoproterenol-Dependent Activation of TRPM7 Protects Against Neurotoxin-Induced Loss of Neuroblastoma Cells

Abstract

Neuronal function and their survival depend on the activation of ion channels. Loss of ion channel function is known to induce neurodegenerative diseases such as Parkinson's that exhibit loss of dopaminergic neurons; however, mechanisms that could limit neuronal loss are not yet fully identified. Our data suggest that neurotoxinmediated loss of neuroblastoma SH-SY5Y cells is inhibited by the addition of βadrenergic receptor (β-AR) agonist isoproterenol. The addition of isoproterenol to SHSY-5Y cells showed increased Mg 2+ influx and cell survival in the presence of neurotoxin especially at higher concentration of isoproterenol. Importantly, isoproterenol potentiated transient receptor potential melastatin-7 (TRPM7) channel activation that leads to an increase in intracellular Mg 2+ levels. The addition of 2APB, which is a known TRPM7 channel blocker, significantly decreased the TRPM7 function and inhibited isoproterenol-mediated protection against neurotoxins. Moreover, neurotoxins inhibited TRPM7 expression and function, but the restoration of TRPM7 expression increased neuroblastoma cell survival. In contrast, TRPM7 silencing increased cell loss, decreased Mg 2+ homeostasis, and inhibited mitochondrial function. Moreover, isoproterenol treatment prevented neurotoxin-mediated loss of TRPM7 expression and inhibited Bax expression that induces cell survival. These effects were dependent on the neurotoxin-induced increase in oxidative stress, which inhibits TRPM7 expression and function. Together, our results suggest a positive role for β-AR in activating TRPM7 channels that regulate Mg 2+ homeostasis and are essential for the survival of SH-SY5Y cells from neurotoxin.

Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7

“…In this study, injection of antitumor carvacrol was found to reduce TRPM7 activity, thereby suppressing tumor growth in the mouse bladder cancer in vivo . Sun and his collaborators recently reported that apoptotic neuronal cell death induced by a Parkinson’s disease-related neurotoxin, MPP + , is protected by TRPM7 activation induced by isoproterenol ( Sun et al, 2020a ) and by TRPM7 overexpression ( Sun et al, 2020b ) in dopaminergic differentiated neuroblastoma SH-SY5Y cells. Moreover, in their in vivo studies, treatment with the neurotoxin, MPTP, was found to cause apoptotic tissue damage together with reduction of the TRPM7 level in mouse substantia nigra pars compacta (SNpc) region ( Sun et al, 2020b ).…”

Magnesium and the Brain: A Focus on Neuroinflammation and Neurodegeneration

“…Transient receptor potential melastatin (TRPM) 7, a ubiquitously expressed ion channel coupled with an α kinase domain, is essential in maintaining intracellular Mg concentrations [83]. It has a role in neurodevelopment at early embryonic stages and coordinates the maturation of neuronal networks at later postnatal stages [84] and the loss of this channel is involved in the onset of neurological diseases [85]. At the cellular level, TRPM7 controls the proliferation and differentiation of neuronal cells and regulates the growth and migration of astrocytes [8].…”

“…Looking at TRPM7, it has been proposed as a candidate susceptibility gene for familial Parkinson's disease [108]. TRPM7 has a fundamental role in the survival of dopaminergic human neuroblastoma SH-SY5Y cells [109], and the suppression of TRPM7 inhibits Mg content and mitochondrial function, inducing cell death [85]. On the contrary, in an experimental model of Parkinson's disease induced by 6-hydroxy-dopamine, the total amounts of TRPM7 are increased [110], and the silencing TRPM7 is neuroprotective in pheochromocytoma PC12 cells [111].…”

Sevoflurane participates in the protection of rat renal ischemia‐reperfusion injury by down‐regulating the expression of TRPM7

“…In the process of brain and myocardial injury, the increased expression of TRPM7 leads to the apoptosis of neurons and cardiomyocytes, while inhibition of TRPM7 can alleviate the stroke and myocardial injury. 18 , 19 However, the expression of TRPM7 in renal ischemia‐reperfusion injury has not been reported in detail. Therefore, this study established a rat model to explore the role of TRPM7 in rat renal ischemia‐reperfusion injury.…”

“…As an ion channel, TRPM7 can nonselectively allow the passage of divalent cations such as calcium and magnesium, thereby depolarizing excitatory cells and leading to intracellular calcium overload; as a kinase, TRPM7 can phosphorylate itself or activate its substrates Annexin AI (AnnexinI1, myosin II and m‐calDain 15–17 ). In the process of brain and myocardial injury, the increased expression of TRPM7 leads to the apoptosis of neurons and cardiomyocytes, while inhibition of TRPM7 can alleviate the stroke and myocardial injury 18,19 . However, the expression of TRPM7 in renal ischemia‐reperfusion injury has not been reported in detail.…”