The atypical ‘hippocampal’ glutamate receptor coupled to phospholipase D that controls stretch‐sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2

Thompson, Karen J.; Watson, Sonia; Zanato, Chiara; Dall'Angelo, Sergio; De Nooij, Joriene C.; Pace‐Bonello, Bethany; Shenton, Fiona C.; Sanger, Helen E.; Heinz, Beverly A.; Broad, Lisa M.; Grosjean, Noelle; McQuillian, Jessica R.; Dubini, Marina; Pyner, Susan; Greig, Iain; Zanda, Matteo; Bleakman, David; Banks, Robert W.; Bewick, Guy S.

Abstract

A metabotropic glutamate receptor coupled to phospholipase D (PLD-mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch-evoked firing. We report here the first identification of this PLD-mGluR protein, by capitalizing on its expression in primary mechanosensory terminals, developing an enriched source, pharmacological profiling to identify an optimal ligand, and then functionalizing it as a molecular tool. Evidence from immunofluorescence, western and far-western blotting indicates PLD-mGluR is homomeric GluK2, since GluK2 is the only glutamate receptor protein/receptor subunit present in spindle mechanosensory terminals. Its expression was also found in the lanceolate palisade ending of hair follicle, also known to contain the PLD-mGluR. Finally, in a mouse model with ionotropic function ablated in the GluK2 subunit, spindle glutamatergic responses were still present, confirming it acts purely metabotropically. We conclude the PLD-mGluR is a homomeric GluK2 kainate receptor signalling purely metabotropically and it is common to other, perhaps all, primary mechanosensory endings.

Citation

Thompson, K. J., Watson, S., Zanato, C., Dall'Angelo, S., De Nooij, J. C., Pace‐Bonello, B., …Bewick, G. S. (2024). The atypical ‘hippocampal’ glutamate receptor coupled to phospholipase D that controls stretch‐sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2. Experimental Physiology, 109(1), 81-99. https://doi.org/10.1113/ep090761

• Journal Article Type: Article
• Acceptance Date: Aug 8, 2023
• Online Publication Date: Sep 1, 2023
• Publication Date: 2024-01
• Deposit Date: Feb 8, 2024
• Publicly Available Date: Feb 8, 2024
• Journal: Experimental Physiology
• Print ISSN: 0958-0670
• Electronic ISSN: 1469-445X
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 109
• Issue: 1
• Pages: 81-99
• DOI: https://doi.org/10.1113/ep090761
• Public URL: https://durham-repository.worktribe.com/output/2229854