Targeting T-type/CaV3.2 channels for chronic pain

Abbreviations: AP = action potentials; CaV3.2 = voltage-gated calcium channel subfamily CaV3.2; CCD = chronic compression of DRG; CCI = chronic constriction injury; Cdk5 = cyclindependent kinase 5; CFA = complete Freund's adjuvant; CIPN = chemotherapy induced peripheral neuropathy; CRMP2 = collapsin response mediator protein; DRG = dorsal root ganglion; Egr-1 = early growth response 1; IGF-1 = insulin-like growth factor 1; HMGB1 = high mobility group box 1; HVA = high voltage-activated; H2S = hydrogen sulfide; LTMR = low-threshold mechanoreceptor; LVA = low-voltage activated; N2O = nitrous oxide; PDN = Peripheral diabetic neuropathy; PMA = phorbol 12-myristate 13-acetate; PKCa = protein kinase Ca; pSNL = partial sciatic nerve ligation; RAGE = receptor for advanced glycation end-products; REST = repressor element 1-silencing transcription factor; SDH = spinal dorsal horn; SNI = spared nerve injury; SNL = spinal nerve ligation; STZ = Streptozotocin; SUMO = small ubiquitin-related modifier; TTX-R = tetrodotoxin-resistant Na+ currents; USP5 = ubiquitin-specific cysteine protease 5/ isopeptidase T; WW1 = WW Domain Containing E3 Ubiquitin Protein Ligase 1 T-type calcium channels regulate neuronal excitability and are important contributors of pain processing. CaV3.2 channels are the major isoform expressed in nonpeptidergic and peptidergic nociceptive neurons and are emerging as promising targets for pain treatment. Numerous studies have shown that CaV3.2 expression and/or activity are significantly increased in spinal dorsal horn and in dorsal root ganglia neurons in different inflammatory and neuropathic pain models. Pharmacological campaigns to inhibit the functional expression of CaV3.2 for treatment of pain have focused on the development of direct channel blockers, but none have produced lead candidates. Targeting the proteins that regulate the trafficking or transcription, and the ones that modify the channels via post-translational modifications are alternative means to regulate expression and function of CaV3.2 channels and hence to develop new drugs to control pain. Here we synthesize data supporting a role for CaV3.2 in numerous pain modalities and then discuss emerging opportunities for the indirect targeting of CaV3.2 channels. (Translational Research 2021; 234:20-30)