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Title: The identification and progress towards isolation of an atypical glutamate receptor in muscle spindle primary afferent nerve terminals
Author: Thompson, Karen Jane
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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Hypertension affects 1 billion individuals worldwide and is the major contributing factor to cardiovascular disease. However, the WHO considers current antihypertensive drug therapies inadequate, highlighting a need for a novel approach to hypertension management. Baroreceptors are a promising drug target, and express an unusual glutamate receptor coupled to phospholipase D (PLD-GluR). The PLD-GluR has not been isolated and characterised, which is an important step towards its use as a drug target. A good source of the PLD-GluR is muscle spindle primary afferent nerve terminals, the largest mechanoreceptor in the body. This study thus focuses upon the identification and progress towards isolation of the PLD-GluR from muscle spindle primary afferent nerve terminals. A novel dissection method for high yield extraction of muscle spindles from a high density source, the rat deep masseter muscle, was developed for Western blotting and mass spectrometry screens of all GluRs. Western blots showed spindle homogenate contained a low molecular weight mGluR5 isoform and GluK2. Immunofluorescence showed mGluR5 was expressed on putative nociceptors, not mechanosensory nerve terminals. However, spindle mechanosensory nerve terminals labelled brightly for GluK2, as did baroreceptor nerve terminals. Furthermore, GluK2 appears to be the only GluR subunit on these mechanoreceptors, although mass spectrometry and affinity chromatography could not successfully isolate this receptor. Finally, piezo2 has recently been suggested as the major mechanotransducer protein. However, no evidence was found for piezo2 expression in adult spindle mechanosensory nerve terminals in adult rats or mice. As previous studies have largely focussed on adolescent mice, this could represent a developmental difference. Conversely, a number of candidate mechanosensory proteins, such as TRPs, were identified by a targeted mass spectrometry approach. This provides good candidates for future research. Collectively, this study indicates both spindle and baroreceptor mechanosensory nerve terminals express GluK2, suggesting it is at least a component of the PLD-GluR, and therefore potentially represents a novel drug target for treating hypertension.
Supervisor: Not available Sponsor: Tenovus Scotland
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Glutamic acid ; Neuromuscular spindles ; Afferent pathways