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Functional Studies of PKD2 and PKD2L1 through Opening the Hydrophobic Activation Gate
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Wang Zheng, Lingyun Wang, Jingfeng Tang, Ji-Bin Peng, Xing-Zhen Chen
The TRPP subfamily contains three members: PKD2 (also called polycystin-2 or TRPP2), PKD2L1 (also called polycystin-L or TRPP3) and PKD2L2 (also called TRPP5). PKD2, the founding member of the TRPP subfamily, is mutated in about 15% of the autosomal dominant polycystic kidney disease (ADPKD) cases; ADPKD is the most common monogenetic disorder of the kidney, affecting over 12.5 million people worldwide.5 The disease is featured by the progressive formation of fluid-filled, enlarged renal cysts, which lead to a decline in the renal function.6 The remaining 85% of the ADPKD cases are caused by mutations in PKD1, which forms a heterotetrameric complex with PKD2 in a stoichiometry of 1:3.7–9 To date, PKD1 and PKD2 have been well characterized to be involved in many signaling pathways related to cell proliferation and apoptosis, two hallmarks of renal cystic cells.10 Dysfunctions of PKD1 and/or PKD2 presumably result in abnormal signaling pathways, which together initiate and promote cyst growth. However, it remains largely unclear as to whether and how the channel function of the PKD2 homotetramer or the PKD1/PKD2 heterotetramer is involved in the disease pathogenesis. Also, there have been controversies about the channel function of PKD2 and the PKD1/PKD2 complex. For instance, PKD2 was initially proposed to be a Ca2+ release channel in the endoplasmic reticulum,11 but recently, increasing evidence suggested that PKD2 has a low permeability, if not impermeable, to Ca2+.12,13 The PKD1/PKD2 complex was previously hypothesized to act as a fluid flow sensor in primary cilia of renal epithelial cells14 and coexpression of PKD1 and PKD2 in CHO cells was reported to give rise to distinct cation currents.15 However, with genetically engineered Ca2+ sensors in the primary cilia, no Ca2+ influx was detected at physiological or even supraphysiological levels of fluid flow.16 Also, by directly measuring currents across primary cilia, PKD2, but not PKD1, was shown to be an essential ion channel subunit in the primary cilium of renal collecting duct epithelial cells.13 In addition, a gain-of-function (GOF) PKD2 mutant F604P was recently found to induce robust cation currents when expressed in Xenopus oocytes,12 but no current was detected when this mutant was expressed in mammalian cells.17 Although high-resolution structures of PKD2 homotetramers and PKD1/PKD2 heterotetramers are now available9,18–20 and they were both revealed to be pore-forming complexes, their channel functions have still remained elusive. Therefore, a reliable and well-recognized function readout is essential to understanding PKD2 channel function.
TRPV1 Antagonist Suppresses Allergic Conjunctivitis in a Murine Model
Published in Ocular Immunology and Inflammation, 2018
Ji Young Kwon, Hyun Soo Lee, Choun-Ki Joo
In mammals, the transient receptor potential (TRP) family of ion channels located on the plasma membrane act as receptors for stimuli. The TRP family consists of six subfamilies: TRPC (canonical: TRPC1~TRPC7); TRPV (vanilloid: TRPV1~TRPV6); TRPM (melastatin: TRPM1~TRPM8); TRPP (polycystin: TRPP2, TRPP3, TRPP5); TRPML (mucolipin: TRPML1~TRPML3); and TRPA (ankyrin: TRPA1).9 Among the TRP family, the immunologic functions of TRPA1 or TRPV1 have been researched in terms of their immunologic functions in the context of allergic disease. In allergic asthma, TRPA1 or TRPV1 yielded increased Th2 cytokine levels and induced the infiltration of eosinophils into the lungs.10,11 In an allergic dermatitis model, TRPA1 or TRPV1 induced the infiltration of inflammatory cells into the skin, increased Th2 cytokine levels, and provoked itching.12–14 In allergic rhinitis, TRPA1 or TRPV1 increased Th2 cytokine levels and promoted histamine-mediated itching. The increased levels of Th2 cytokines also led to the infiltration of inflammatory cells.15,16