A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy

• Published in: Pain (Amsterdam) Vol. 160; no. 12; pp. 2798 - 2810
• Main Authors: Gaifullina, Aisylu S., Lazniewska, Joanna, Gerasimova, Elena V., Burkhanova, Gulshat F., Rzhepetskyy, Yuriy, Tomin, Andriy, Rivas-Ramirez, Paula, Huang, Junting, Cmarko, Leos, Zamponi, Gerald W., Sitdikova, Guzel F., Weiss, Norbert
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01-12-2019
• Subjects: Animals; Calcium - metabolism; Calcium Channels, T-Type - metabolism; Cell Membrane - metabolism; Disease Models, Animal; Ganglia, Spinal - metabolism; Homocysteine - blood; Hyperalgesia - etiology; Hyperalgesia - metabolism; Hyperhomocysteinemia - complications; Nociception - physiology; Peripheral Nervous System Diseases - etiology; Peripheral Nervous System Diseases - metabolism; Rats; Rats, Wistar
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1097/j.pain.0000000000001669

Homocysteinemia is a metabolic condition characterized by abnormally high level of homocysteine in the blood and is considered to be a risk factor for peripheral neuropathy. However, the cellular mechanisms underlying toxic effects of homocysteine on the processing of peripheral nociception have not yet been investigated comprehensively. Here, using a rodent model of experimental homocysteinemia, we report the causal association between homocysteine and the development of mechanical allodynia. Homocysteinemia-induced mechanical allodynia was reversed on pharmacological inhibition of T-type calcium channels. In addition, our in vitro studies indicate that homocysteine enhances recombinant T-type calcium currents by promoting the recycling of Cav3.2 channels back to the plasma membrane through a protein kinase C-dependent signaling pathway that requires the direct phosphorylation of Cav3.2 at specific loci. Altogether, these results reveal an unrecognized signaling pathway that modulates the expression of T-type calcium channels, and may potentially contribute to the development of peripheral neuropathy associated with homocysteinemia.