生理学报 Acta Physiologica Sinica, October25,2017,695):677-684 partial agonist titive antagonist JYL827 and JYL1511 JYL1421 Na’,c cellula hosphorylational modification TRPV1 ntracellula Cdk5 PKD1 PKA, PKC and CaMKll et membrane localization motor protein Cdk5 cytoskeleton near the plasma membrane KF13B+T506 Tat-T506 actin polymerization post-Golgi trafficking icles cont TRPV1 Tat-S3 图1.本研究组关于TRPV1外周调控机制的工作总结图 Fig. 1. Summary of the studies on the regulatory mechanisms of peripheral TRPVI in our lab. TRPVI can be phosphory lated by rotein kinases, including Cdk5 and PKDl, and the anchoring of these protein kinases on the cytoskeleton is modulated by LIMK. On the other hand, Cdks can phosphorylate the motor protein KIF13B and promotes the membrane trafficking of TRPVI. Application of the technique of Tat-transmembrane peptide can specifically disrupt the above phosphorylation process. In addition, our lab partici- pated in the development of the partial agonists of TRPV1, JYL827 and JYL1511, and the competitive antagonist JYL1421. CaMKll, alcium-calmodulin dependent kinase Il; Cdk5, cyclin-dependent kinase 5; KIF 13B, kinesin-like protein 13B; LIMK, LIM-motif containing kinase; PKA, protein kinase A; PKC, protein kinase C; PKDl, protein kinase DI; Tat-T506, Tat-KIF13B-T506 Tat-T406 Tat-TRPV1-T406: Tat-S3. Tat-cofilin-S3 参考文献 therapy for management of chronic pain: from bench to I Williams AC, Craig KD. Updating the definition of pain. bedside. Lancet Neurol 2013: 12(11): 1084-1095 Pan2016;157(11):2420-2423 8 Julius D. TRP channels and pain. Annual Rev Cell Dev biol 2 Goldberg DS, McGee SJ, Pain as a global public health priority. BMC Public Health 2011; 11: 770 9 Caterina M, Leffler A, Malmberg AB, Martin WJ, Trafton J 3 Knaster P, Karlsson H, Estlander AM, Kalso E Psychiatric Petersen-Zeitz KR, Koltzenburg M, Basbaum Al, Julius D disorders as assessed with SCid in chronic pain patients: the Impaired nociception and pain sensation in mice lacking the anxiety disorders precede the onset of pain. Gen Hosp capsaicin receptor. Science 2000; 288(5464): 306-313 Psychiatry2012;34(1):46-52 10 Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Nociceptor sensitization in pain Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, pathogenesis. Nat Med 2010: 16(11): 1248-1257 Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers 5 Kuner R Central mechanisms of pathological pain. Nat Med DC, Bingham S, Randall A, Sheardown SA Vanilloid recep- 2010,16(11):1258-1266 tor-l is essential for inflammatory thermal hyperalgesia 6 Rask-Andersen M, Zhang j, Fabbro D, HB. Advances ature2000,405(6783):183-187 in kinase targeting: current clinical 11 Park U, Vastani N, Guan Y, Raja SN, Koltzenburg M, Caterina Trends Pharmacol Sci 2014; 35(11): 604-620 MJ. TRP vanilloid 2 knock-out mice are susceptible to peri- 7 Gilron I, Jensen TS, Dickenson AH Combination pharmaco- natal lethality but display normal thermal and mechanical682 生理学报 Acta Physiologica Sinica, October 25, 2017, 69(5): 677–684 参考文献 1 Williams AC, Craig KD. Updating the definition of pain. Pain 2016; 157(11): 2420–2423. 2 Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health 2011; 11: 770. 3 Knaster P, Karlsson H, Estlander AM, Kalso E. Psychiatric disorders as assessed with SCID in chronic pain patients: the anxiety disorders precede the onset of pain. Gen Hosp Psychiatry 2012; 34(1): 46–52. 4 Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat Med 2010; 16(11): 1248–1257. 5 Kuner R. Central mechanisms of pathological pain. Nat Med 2010; 16(11): 1258–1266. 6 Rask-Andersen M, Zhang J, Fabbro D, Schioth HB. Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci 2014; 35(11): 604–620. 7 Gilron I, Jensen TS, Dickenson AH. Combination pharmaco￾therapy for management of chronic pain: from bench to bedside. Lancet Neurol 2013; 12(11): 1084–1095. 8 Julius D. TRP channels and pain. Annual Rev Cell Dev Biol 2013; 29: 355–384. 9 Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288(5464): 306–313. 10 Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA. Vanilloid recep￾tor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405(6783): 183–187. 11 Park U, Vastani N, Guan Y, Raja SN, Koltzenburg M, Caterina MJ. TRP vanilloid 2 knock-out mice are susceptible to peri￾natal lethality but display normal thermal and mechanical 图 1. 本研究组关于TRPV1外周调控机制的工作总结图 Fig. 1. Summary of the studies on the regulatory mechanisms of peripheral TRPV1 in our lab. TRPV1 can be phosphorylated by protein kinases, including Cdk5 and PKD1, and the anchoring of these protein kinases on the cytoskeleton is modulated by LIMK. On the other hand, Cdk5 can phosphorylate the motor protein KIF13B and promotes the membrane trafficking of TRPV1. Application of the technique of Tat-transmembrane peptide can specifically disrupt the above phosphorylation process. In addition, our lab partici￾pated in the development of the partial agonists of TRPV1, JYL827 and JYL1511, and the competitive antagonist JYL1421. CaMKII, calcium-calmodulin dependent kinase II; Cdk5, cyclin-dependent kinase 5; KIF13B, kinesin-like protein 13B; LIMK, LIM-motif containing kinase; PKA, protein kinase A; PKC, protein kinase C; PKD1, protein kinase D1; Tat-T506, Tat-KIF13B-T506; Tat-T406, Tat-TRPV1-T406; Tat-S3, Tat-cofilin-S3