PMID- 29263248
OWN - NLM
STAT- MEDLINE
DCOM- 20180717
LR  - 20190118
IS  - 2046-2441 (Electronic)
IS  - 2046-2441 (Linking)
VI  - 7
IP  - 12
DP  - 2017 Dec
TI  - Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic 
      neuroendocrine tumour cells.
LID - 10.1098/rsob.170221 [doi]
LID - 170221
AB  - 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.
CI  - (c) 2017 The Authors.
FAU - Robinson, Hugh P C
AU  - Robinson HPC
AUID- ORCID: 0000-0002-5048-9954
AD  - Department of Physiology, Development and Neuroscience, University of Cambridge, 
      Downing Street, Cambridge CB2 3EG, UK hpcr@cam.ac.uk.
FAU - Li, Leanne
AU  - Li L
AUID- ORCID: 0000-0002-1598-1564
AD  - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute 
      of Technology, 500 Main Street, Cambridge, MA 02142, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Open Biol
JT  - Open biology
JID - 101580419
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Action Potentials
MH  - Animals
MH  - *Autocrine Communication
MH  - Calcium Signaling
MH  - Cell Line
MH  - Glutamic Acid/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Necrosis
MH  - Neuroendocrine Tumors/*metabolism/pathology
MH  - Pancreatic Neoplasms/*metabolism/pathology
MH  - *Paracrine Communication
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
PMC - PMC5746548
OTO - NOTNLM
OT  - glutamate diffusion
OT  - pancreas cancer
OT  - single-channel recording
COIS- We declare we have no competing interests.
EDAT- 2017/12/22 06:00
MHDA- 2018/07/18 06:00
PMCR- 2017/12/20
CRDT- 2017/12/22 06:00
PHST- 2017/09/28 00:00 [received]
PHST- 2017/11/23 00:00 [accepted]
PHST- 2017/12/22 06:00 [entrez]
PHST- 2017/12/22 06:00 [pubmed]
PHST- 2018/07/18 06:00 [medline]
PHST- 2017/12/20 00:00 [pmc-release]
AID - rsob.170221 [pii]
AID - rsob170221 [pii]
AID - 10.1098/rsob.170221 [doi]
PST - ppublish
SO  - Open Biol. 2017 Dec;7(12):170221. doi: 10.1098/rsob.170221.