Lysosomal ion channel TRPML1 contributes to neuropathic pain associated with diabetic peripheral neuropathy in mice

Authors:
  • YYYuanhong Yang
    Yuanhong Yang
  • STSilin Teng
    Silin Teng
  • YZYihong Zhang
    Yihong Zhang
  • YJYong-Hua Ji
    Yong-Hua Ji
  • HWHongjie Wang
    Hongjie Wang
  • ZTZhi-Yong Tan
    Zhi-Yong Tan
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Abstract
Neuropathic pain associated with diabetic peripheral neuropathy (DPN) is a common and hard-to-treat complication of Diabetes. Ion channels of plasma membrane are major mechanisms and targets for DPN pain. The current study explores the role of a major lysosomal ion channel TRPML1 in DPN pain. Mouse models of DPN pain and TRPML1 knockout were combined with pharmacological inhibition and detection of molecular expression and function. Major findings included: 1) BKS db/db increased expression and function of TRPML1 in dorsal root ganglion (DRG); 2) Lysosomes of DRG neurons expressed functional TRPML1 currents; 3) Global knockout (gKO) or conditional knockout (cKO) in DRG neurons of TRPML1 prevented mechanical allodynia in male mice fed with high fat diet; 4) A TRPML1 inhibitor significantly reversed mechanical allodynia in BKS db/db mice through intraperitoneal injection, and in STZ mice through intrathecal injection; 5) gKO or astrocyte cKO of TRPML1 prevented STZ-induced mechanical allodynia in male and female mice. The results suggest that TRPML1 in DRG neurons and astrocytes contributes to type 2 and type 1 DPN pain, respectively. The current study may serve as a proof-of-concept to explore the role of lysosomal ion channels in painful DPN, painless DPN, and chronic pain.
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