Reversal of Neuropathic Pain in Diabetes by Targeting Glycosylation of Cav3.2 T-Type Calcium Channels
| Autor: | Sang Soo Lee, Katiresan Krishnan, Nathan Poiro, JeongHan Lee, William E. McIntire, Douglass F. Covey, Miljen M. Jagodic, Peihan Orestes, Jung-Ha Lee, Megan O. Jacus, Slobodan M. Todorovic, Vesna Jevtovic-Todorovic, Michael R. DiGruccio, WonJoo Choe, Hari Prasad Osuru, Reza Salajegheh, Kirstin E. Rose, Paula Q. Barrett |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Complications Glycosylation Endocrinology Diabetes and Metabolism 03 medical and health sciences Calcium Channels T-Type 0302 clinical medicine Diabetic Neuropathies Internal medicine Internal Medicine medicine Animals Humans Patch clamp Sensitization 030304 developmental biology Original Research 0303 health sciences Voltage-dependent calcium channel Chemistry T-type calcium channel 3. Good health medicine.anatomical_structure Endocrinology Nociception Hyperalgesia Neuropathic pain Nociceptor Neuralgia medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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 leptin-deficient (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. |
| Databáze: | OpenAIRE |
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