| Human immunodeficiency virus type I(HIV-1)infection is usually accompanied by systemic pain syndrome but the molecular mechanism involved is not clear.HIV-1transcriptional trans-activator Tat protein plays an important role in central nervous system diseases.There is a key helix in the full length structure of HIV-1 Tat,and proteins containing this helix are known to be involved in the pain-causing mechanism by regulating sodium channels.Therefore,we hypothesized that Tat helical-like peptides were involved in the occurrence and development of pain in HIV-1 patients.The behavior of two peptide solutions(49-57)and(48-59)in which HIV-1 Tat helical structures was injected into the center of SD rats foot was detected,and the modulation effect of the above two peptides on the sodium ion channel was investigated by single-cell patch clamp technique.The main results were as follows:1.HIV-1 Tat-like polypeptide can cause acute pain and inflammationThe inflammatory pain model was established by injecting 50,150,450,or 600μg of HIV-1 Tat(49-57)like polypeptides or HIV-1Tat(48-59)like polypeptides into the right hind foot of the rats.The pain sensitive reactions of spontaneous pain and mechanical pain and the swelling degree of inflammatory reaction of right hind foot in rats within 2hours after injection of different doses of Tat-like polypeptide were detected.The results showed that HIV-1 Tat(49-57)and HIV-1 Tat(48-59)like polypeptides can induce local pain and inflammation in rats.All these results are consistent with the reported effects of a significant decrease in the threshold of foot contraction from the fourth week in full-length HIV-1Tat transgenic mice.Therefore,we speculate that HIV-1 Tat(49-57)and HIV-1 Tat(48-59)may be the important structural regions of Tat induced pain and inflammation.2.HIV-1 Tat-like polypeptide has the effects of increasing Na~+peak current of cellsElectrophysiological patch clamp technique was used to record the sodium current change effect of HEK293T cells and ND7/23 cells within 15 minutes after HIV-1 Tat(49-57)and(48-59)like polypeptides were added.The results showed that both HIV-1Tat(49-57)and HIV-1 Tat(48-59)increased the peak currents of HEK293T and ND7/23cells.HIV-1 Tat(49-57)like polypeptide has a dose-dependent effect on increasing the total Na~+peak current in ND7/23 cells.The Tat(49-57)like polypeptide also significantly facilitated the activation of full Na~+current in ND7/23 cells.100 nM Tat(49-57)like polypeptide can facilitate the activation of HEK293T cell current.Tat(48-59)can facilitate the activation of Na~+current and delay the deactivation of current in ND7/23cells.These results are basically consistent with the modulation effect of Tat full-length protein on the total Na~+current of intestinal neurons.Therefore,we speculate that the helical structure of Tat protein is an important functional element in the mechanism of action of Tat full-length protein regulating Na~+channel.Tat(49-57)and Tat(48-59)have the similar effect of regulating Na~+current of cells with full-length Tat protein.Through the animal behavior test,HIV-1 Tat(49-57)and HIV-1 Tat(48-59)have the effect of inducing pain and inflammation in rats,which is basically consistent with the reported results of pain caused by full-length Tat protein.Therefore,we believe that the key helix structure of HIV-1 Tat is the key structural region in the mechanism of Tat protein regulating Na~+current and causing pain.The results of this study provide a new way for further study of HIV-1 Tat virus protein and other virus proteins,improving or solving the pain problems of AIDS patients and even for treating a series of central nervous system and other related diseases caused by AIDS. |
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