Reversal of neuropathic pain in diabetes by targeting glycosylation of Cav3.2 T-type calcium channels

Peihan Orestes, Hari Prasad Osuru, William E. McIntire, Megan O. Jacus, Reza Salajegheh, Miljen M. Jagodic, Won Joo Choe, Jeong Han Lee, Sang Soo Lee, Kirstin E. Rose, Nathan Poiro, Michael R. DiGruccio, Katiresan Krishnan, Douglas F. Covey, Jung Ha Lee, Paula Q. Barrett, Vesna Jevtovic-Todorovic, Slobodan M. Todorovic

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

It has been established that CaV3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of CaV3.2 T-channel in a leptindeficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in CaV3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of CaV3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN.

Original languageEnglish
Pages (from-to)3828-3838
Number of pages11
JournalDiabetes
Volume62
Issue number11
DOIs
StatePublished - Nov 2013

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