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TRPV1 sensitivity in nociceptors"
Pharmacology & Physiology Program
M.D., Semmelweis University of Medicine
Thesis Advisor: Tibor Rohacs, M.D., Ph.D. Associate Professor
Department of Pharmacology & Physiology
Wednesday, April 17, 2013
12:00 P.M., MSB Room H-609
The capsaicin receptor TRPV1 is a polymodal, Ca2+-permeable cation channel that plays a crucial role in regulating nociceptor responsiveness. Sensitization of TRPV1 by G]protein coupled receptor (GPCR) activation is a key factor in inducing hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 leads to calcium influx]induced adaptation of the channel and diminished nociceptor firing.
Many of the pro]inflammatory agents responsible for inducing hyperalgesia and pain act via the Gq] and phospholipase C (PLC) pathway, leading to hydrolysis of phosphatidylinositol](4,5)]bisphosphate [PI(4,5)P2] as well as phosphorylation of TRPV1 by protein kinase C (PKC). Interestingly, we have shown that agonist]induced desensitization of the channel also involves activation of PLC. Thus, in both cases hydrolysis of phosphoinositides is expected to ensue, yet these conditions result in strikingly different outcomes in terms of TRPV1 activity and neuronal responsiveness. Phosphoinositides have emerged as important regulators of TRPV1; their role is, however, also controversial. The aim of our study is to attempt to clarify these controversies by studying the dynamic changes of phosphoinositides and selectively manipulating their levels in heterologous systems as well as in DRG neurons.
Our findings show that PI(4,5)P2 and its precursor PI(4)P are both sufficient to support TRPV1 function via membrane]delimited activation of the channel, but PI(4,5)P2 also exerts an additional inhibitory effect on TRPV1 in a whole]cell setting by inhibiting the effects of PKC]dependent channel regulation. High concentration capsaicin treatment induces a robust depletion of both PI(4,5)P2 and PI(4)P in DRG neurons, which limits TRPV1 function and leads to agonist]induced channel desensitization. On the other hand, bradykinin receptor activation produces an isolated decrease in PI(4,5)P2 but not PI(4)P levels, a condition that does not limit TRPV1 currents but results in increased effectiveness of PKC]mediated potentiation of TRPV1 and therefore contributes to inflammatory TRPV1 sensitization.
Taken together, PI(4)P and PI(4,5)P2 are important endogenous regulators of TRPV1. Distinct changes in the abundance of these lipids in response to pathological conditions or pharmacological treatment result in opposing regulation of TRPV1 responsiveness.