The system involved in mechanotransduction by proprioceptive sensory organs, such as muscle spindles, is poorly understood. We previously reported that stretch releases glutamate from synaptic-like vesicles (SLVs) within muscle spindle terminals (the proprioceptive sensory organs of muscles), and activates a non-canonical mGluR, modulating afferent firing (Bewick et al, 2005). If, as our previous data and the literature suggests, this system is present in other mechanosensory endings, such as baroreceptors, it presents a drugable target in the treatment of hypertension. With current hypertension therapy ineffective in around 20% of patients a novel target such as this is highly important to investigate. This study aimed to further investigate this receptor's pharmacology by screening ligands selective for classical mGluRs for their ability to alter stretch-evoked spindle firing in muscle spindles and SLV uptake in lanceolate endings. I found that although there are differences between the two systems, overall the pharmacology most closely matches that of the currently unsequenced phospholipase D coupled mGluR previously studied in the hippocampus (Pellegrini-Giampietro et al., 1996). Furthermore the pharmacology does not match that of any canonical mGluR (or iGluR). This pharmacological profiling allowed the development of novel kainate-derived compounds which were tested to find more potent analogues suitable for “click chemistry” (Kolb et al, 2001). The development of these compounds allowed further compounds to be synthesised with biotin and fluorescent side chains which will be used in further studies ultimately to allow sequencing of the receptor. In respect to baroreceptors I expanded our data in the working-heart-brainstem model and developed an isolated aortic preparation which will be used in further studies to further characterise this SLV/glutamate system in baroreceptors.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:648911 |
| Date | January 2015 |
| Creators | Watson, Sonia |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=225803 |
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