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Pharmacological characterisation of recombinant vanilloid receptors

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posted on 15.12.2014, 10:34 by Patricia May Wah Lam
In HEK cells expressing human and rat isoforms of TRPV1, capsaicin, anandamide (an endocannabinoid), olvanil (a structural analogue of capsaicin) and ethanol displayed TRPV1 activity. in contrast, Delta9-THC (an exocannabinoid) did not. No significant difference occurred between human and rat with respect to capsaicin and anandamide activity at 22ºC or 37ºC. Anandamide displayed partial agonism relative to capsaicin at both temperatures at rat only. Anandamide was also an agonist at cannabinoid CB1 receptors. Capsazepine, a competitive TRPV1 antagonist, inhibited capsaicin, olvanil and anandamide response; was not temperature-dependent but displayed a 6-fold higher potency at human TRPV1.;The first neuronal model to express recombinant human TRPV1 was produced by sub-cloning and transfection into the neuroblastoma SH-SY5Y cell-line, a more physiologically relevant system. Pharmacological characterisation confirmed expression of TRPV1 with comparable pharmacology to non-neuronal models in this thesis. For example, capsaicin pEC50/capsazepine pKB in HEk (human TRPV1) and SH-SY5Y were 6.77/6.75 and 6.63/7.44 respectively. In SH-SY5Y cells, the agonist resiniferatoxin displayed the highest potency (pEC50 9.03). Iodo-RTX, an antagonist, revealed a higher affinity than capsazepine. Capsaicin-mediated increases in intracellular calcium (pEC50 6.63) in SH-SY5Y cells were sufficient to sustain [3H]noradrenaline release (pEC50 9.21). In a perfusion system, it was shown that the two events were temporally linked.;Overall, these findings have: 1. expanded current knowledge of TRPV1 pharmacology. 2. established a neuronal model for further studies, especially TRPV1 desensitisation.


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Cardiovascular Sciences

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University of Leicester

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