title: Reversal of neuropathic pain in diabetes by targeting glycosylation of Ca(V)3.2 T-type calcium channels.
abstract: It has been established that Ca(V)3.2 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 Ca(V)3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in Ca(V)3.2 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 Ca(V)3.2 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.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Peihan
authors.initials: P
authors.lastname: Orestes
authors.forename: Hari Prasad
authors.initials: HP
authors.lastname: Osuru
authors.forename: William E
authors.initials: WE
authors.lastname: McIntire
authors.forename: Megan O
authors.initials: MO
authors.lastname: Jacus
authors.forename: Reza
authors.initials: R
authors.lastname: Salajegheh
authors.forename: Miljen M
authors.initials: MM
authors.lastname: Jagodic
authors.forename: Wonjoo
authors.initials: W
authors.lastname: Choe
authors.forename: Jeonghan
authors.initials: J
authors.lastname: Lee
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Lee
authors.forename: Kirstin E
authors.initials: KE
authors.lastname: Rose
authors.forename: Nathan
authors.initials: N
authors.lastname: Poiro
authors.forename: Michael R
authors.initials: MR
authors.lastname: Digruccio
authors.forename: Katiresan
authors.initials: K
authors.lastname: Krishnan
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Jung-Ha
authors.initials: JH
authors.lastname: Lee
authors.forename: Paula Q
authors.initials: PQ
authors.lastname: Barrett
authors.forename: Vesna
authors.initials: V
authors.lastname: Jevtovic-Todorovic
authors.forename: Slobodan M
authors.initials: SM
authors.lastname: Todorovic
mesh_terms: D000818:Animals; D001216:Asparagine / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D006031:Glycosylation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D051379:Mice; D008820:Mice, Obese; D009437:Neuralgia / Q000188:drug therapy*; D009439:Neuraminidase / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects; D018408:Patch-Clamp Techniques; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000378:metabolism; D011994:Recombinant Proteins; D014162:Transfection
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D011994:Recombinant Proteins; D001216:Asparagine; D009439:Neuraminidase; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase