Abstract
N-Methyl-d-aspartate receptor (NMDAR) activation is implicated in the malignant progression of many cancer types, as previously shown by the growth-inhibitory effects of NMDAR antagonists. NMDAR-mediated calcium influx and its downstream signalling depend critically, however, on the dynamics of membrane potential and ambient glutamate concentration, which are poorly characterized in cancer cells. Here, we have used low-noise whole-cell patch-clamp recording to investigate the electrophysiology of glutamate signalling in pancreatic neuroendocrine tumour (PanNET) cells derived from a genetically-engineered mouse model (GEMM) of PanNET, in which NMDAR signalling is known to promote cancer progression. Activating NMDARs caused excitation and intracellular calcium elevation, and intracellular perfusion with physiological levels of glutamate led to VGLUT-dependent autocrine NMDAR activation. Necrotic cells, which are often present in rapidly-growing tumours, were shown to release endogenous cytoplasmic glutamate, and necrosis induced by mechanical rupture of the plasma membrane produced intense NMDAR activation in nearby cells. Computational modelling, based on these results, predicts that NMDARs in cancer cells can be strongly activated in the tumour microenvironment by both autocrine glutamate release and necrosis.
Highlights
The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor which is present at most excitatory glutamatergic synapses in the nervous system [1,2]
Do NMDARs mediate significant membrane current and calcium influx? What are the sources of their main ligand, glutamate, for their activation in cancer cells? Are NMDARs activated by autocrine or paracrine glutamate secretion, or both? Using the RIP1-Tag2 mouse model of pancreatic neuroendocrine tumour (PanNET) [11], Li & Hanahan [12] showed that NMDAR activation is associated with invasive tumour growth, and proposed a model in which autocrine release of glutamate, stimulated by interstitial fluid flow, causes & 2017 The Authors
We used an intracellular solution in which potassium was replaced by caesium, to reduce baseline noise [15] and allow single-channel resolution in the whole-cell current [16], and magnesium was omitted from the extracellular solution, to prevent magnesium block of NMDARs
Summary
The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor which is present at most excitatory glutamatergic synapses in the nervous system [1,2]. It is calcium-permeable, but blocked in a voltage-dependent way by extracellular magnesium ions. Using the RIP1-Tag mouse model of pancreatic neuroendocrine tumour (PanNET) [11], Li & Hanahan [12] showed that NMDAR activation is associated with invasive tumour growth, and proposed a model in which autocrine release of glutamate, stimulated by interstitial fluid flow, causes Do NMDARs mediate significant membrane current and calcium influx? What are the sources of their main ligand, glutamate, for their activation in cancer cells? Are NMDARs activated by autocrine or paracrine glutamate secretion, or both? Using the RIP1-Tag mouse model of pancreatic neuroendocrine tumour (PanNET) [11], Li & Hanahan [12] showed that NMDAR activation is associated with invasive tumour growth, and proposed a model in which autocrine release of glutamate, stimulated by interstitial fluid flow, causes
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