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Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells
Hugh P C Robinson1, Leanne Li2
1Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK hpcr@cam.ac.uk.
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.
Insights
N-Methyl-D-aspartate receptor (NMDAR) activation promotes cancer progression. Cancer cells utilize autocrine glutamate release and necrosis to activate NMDARs, influencing tumor microenvironment dynamics.
Area of Science:
- Oncology
- Neuroscience
- Molecular Biology
Background:
- N-Methyl-D-aspartate receptor (NMDAR) activation is linked to cancer progression, but its signaling dynamics in cancer cells remain unclear.
- Understanding glutamate concentration and membrane potential is crucial for NMDAR-mediated calcium influx and downstream signaling in tumors.
Purpose of the Study:
- To investigate the electrophysiology of glutamate signaling in pancreatic neuroendocrine tumor (PanNET) cells.
- To characterize NMDAR activation mechanisms within the tumor microenvironment.
Main Methods:
- Whole-cell patch-clamp recording in a genetically-engineered mouse model (GEMM) of PanNET.
- Investigated glutamate signaling, calcium influx, and NMDAR activation.
- Utilized computational modeling to predict NMDAR activity.
Main Results:
- NMDAR activation in PanNET cells led to excitation and calcium elevation.
- Vesicular glutamate transporter (VGLUT)-dependent autocrine NMDAR activation occurred with physiological glutamate levels.
- Necrotic cancer cells released glutamate, causing significant NMDAR activation in adjacent cells.
Conclusions:
- NMDARs are activated in cancer cells via autocrine glutamate release and necrosis.
- These mechanisms contribute to NMDAR activation within the tumor microenvironment.
- Findings elucidate critical signaling pathways in PanNET progression.
