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

Abstract

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.

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

“…Plasma homocysteine levels ranging from 15 to 30 μM cause mild hHcy, 31 to 100 μM—moderate hHcy or >100 μM—severe hHcy symptoms [ 23 ]. An elevated level of homocysteine induces endothelial dysfunctions, oxidative stress, or inflammation and is associated with several pathological states like neurological disorders, chronic kidney disease, osteoporosis, gastrointestinal disorders, cancer, or congenital defects [ 24 , 25 , 26 ]. Increased homocysteine levels during pregnancy result in preeclampsia, fetus pathologies or growth restriction due to endothelial dysfunctions of the placenta [ 27 ].…”

The Association Between Retinal Vessel Abnormalities and H-type Hypertension

“…The conclusion was that hypertension was closely associated with HCY [9]. According to previous ndings, a high level of HCY did harm to systemic vascular endothelial cells [10,11]. Elsherbiny et al further demonstrated that HHCY can undermine inner and outer blood-retinal barriers [12].…”

“…HCY is converted to cysteine and eventually metabolizes in the body to produce H 2 S in the process. Accumulating evidence indicated that H 2 S is a physiological vasorelaxant and reduced production of H 2 S in the vascular tissue leads to hypertension [11,21,22]. Besides, HHCY may cause direct toxicity and vascular endothelial injury, which may induce hypertension or aggravating the damage of hypertension to vessels [23][24][25].…”

Transcriptomic analysis of glycan-processing genes in the dorsal root ganglia of diabetic mice and functional characterization on Cav3.2 channels

“…Increased expression of Ca v 3.2 in primary afferent nociceptive fibers is causally linked to the development of peripheral painful neuropathy associated with nerve injury [18][19][20], antineoplastic drugs [21][22][23], inflammation [24,25], and diabetes [1,3]. Several studies have unraveled some of the mechanisms underlying the pathological expression of Ca v 3.2 and alteration of the posttranslational regulation of the channel including ubiquitinylation [26], SUMOylation [27] and phosphorylation [28,29]. Defects in these processes have emerged as some of the primary reasons leading to enhanced expression of the channel.…”