Concentration-dependent Desensitization Of Nociceptor TRPV1 Ion Channel

The capsaicin receptor TRPV1, a non-selective cation permeable ion channel with consequential function in nociception at peripheral nervous system, is desensitized after calcium influx induced by activation of the channel by capsaicin. PIP2(Phosphatidylinositol 4,5-bisphosphate), as reported in many researches, possess magnificent function in maintaining the activity of TRPV1 channel, the hydrolysis of which shows important role in the desensitization of TRPV1 channel. Adaptation is a hallmark of nociceptors which indicates that the TRPV1 channel preserve a full response to agonist stimuli after channel desensitization. However, it has not been clearly described whether there is a synergic effect responsible for the functional regulation accompanying desensitization of TRPV1 channels and whether the extent of desensitization could change during hyperalgesia.By using capsaicin at over saturate concentration combined with extracellular Ca2+ during the desensitization of TRPV1 channels, we observed and confirmed a potentiated extent of desensitization, followed by an activity loss of response to capsaicin stimuli, which suggests that the extent of desensitization is agonist concentration dependent. And the ratio and extent of desensitization of TRPV1 channel is decreased if the intracellular Ca2+ concentration is lowered, which illustrates that the extent of desensitization is corresponding to the efficiency of Ca2+ influx during desensitization. Through subsequent experiments, we examined whether the intracellular cascades, like dephosphorylation, phosphoinositide depletion and endocytosis have contribution in the concentration-dependent desensitization of TRPV1 channels.The subsequent analysis on capsaicin dose-response relation corroborated our results that the activity loss following potentiated desensitization could not be recovered by replenishment of PIP2, the depletion of which account for the capsaicin sensitivity reduction during normal desensitization. Admittedly, the channel gating maintained consistent at normally or excessively desensitized status and the resting status. We then analyzed other Ca2+-dependent processes probably corresponding to the potentiated desensitization and ruled out the involvement of dephosphorylation and endocytosis.These results pinpointed that the extent of TRPV1 desensitization is dependent on the concentration of agonists during desensitization and the efficiency of Ca2+ influx exhibit an essential role in the ratio and extent of TRPV1 channel desensitization. Admittedly, the subsequent analysis confirmed the contribution of PIP2 in agonist sensitivity reduction, other than in activity loss during potentiated desensitization. Clarifying the different extents of desensitization of TRPV1 channels and underlying causal factor help to illustrate the role of TRPV1 channel in plasticity of pain sensation.