Regulation of T‐type Ca²⁺ channel expression by interleukin‐6 in sensory‐like ND7/23 cells post‐herpes simplex virus (HSV‐1) infection

Abstract

Herpes simplex virus‐type 1 (HSV‐1) infection of sensory neurons may lead to a significant reduction in the expression of voltage‐activated Na+ and Ca2+ channels, which can disrupt the transmission of pain information. Viral infection also results in the secretion of various pro‐inflammatory cytokines, including interleukin (IL)‐6. In this work, we tested whether IL‐6 regulates the expression of Na+ and Ca2+ channels post‐HSV‐1 infection in ND7/23 sensory‐like neurons. Our results demonstrate that HSV‐1 infection causes a significant decrease in the protein expression of the Cav3.2 T‐type Ca2+ channel subunit, despite increasing Cav3.2 mRNA synthesis. Neither Cav3.2 mRNA nor total protein content was affected by IL‐6 treatment post‐HSV‐1 infection. In ND7/23 cells, HSV‐1 infection caused a significant reduction in the expression of Na+ and T‐type Ca2+ channels within 48 h. Exposure of ND7/23 cells to IL‐6 for 24 h post‐infection reverses the effect of HSV‐1, resulting in a significant increase in T‐type Ca2+ current density. However, Na+ currents were not restored by 24‐h treatment with IL‐6 post‐HSV‐1 infection of ND7/23 cells. The ability of IL‐6 to increase the functional expression of T‐type Ca2+ channels on the membrane was blocked by the inhibition of protein trafficking with brefeldin‐A and ERK1/2 activation. These results indicate that IL‐6 release following HSV‐1 infection regulates the expression of T‐type Ca2+ channels, which may alter the transmission of pain information.

Host Calcium Channels and Pumps in Viral Infections

“…In addition, herpes simplex virus (HSV)-1 could downregulate the VGCCs on infected neuronal cells to escape detection by host cells. T-type Ca 2+ channels were reported as the targets of HSV-1 in sensory-like ND7-23 cells [19,20]. HSV-1 infection of differentiated ND7-23 cells causes a significant loss of T-type Ca 2+ channels from the membrane, which depends on viral replication and protein synthesis.…”

“…HSV-1 HSV-1 downregulates the Ca V 3.2 channel and diminishes the detection of viral infection by host [19,20].…”

Gate-keeper of ion transport—a highly conserved helix-3 tryptophan in a channelrhodopsin chimera, C1C2/ChRWR

“…The ND7/23 cells were grown in Dulbecco’s modified Eagle’s medium (FUJIFILM Wako Pure Chemical Co., Osaka, Japan) supplemented with 5% fetal bovine serum under a 5% CO 2 atmosphere at 37°C. Twenty-four hours before the transfection, the cells were dissociated and re-plated onto collagen-coated coverslips (4912-010, AGC Techono Glass Co., Yoshida-Shizuoka, Japan), and the medium was replaced by Opti-MEM medium (Thermo Fisher Scientific Inc., Waltham, MA) containing 15% KnockOut TM Serum Replacement (Thermo Fisher Scientific Inc.), 50 ng/mL nerve growth factor-7S (Sigma-Aldrich, St. Louis, MO), and 1 mM N 6 ,2'-O-dibutyryladenosine-3',5'-cyclic monophosphate sodium salt (Nacalai tesque, Kyoto, Japan), as previously described [ 34 ]. The expression plasmids were transiently transfected in ND7/23 cells using Lipofectamine TM 2000 transfection reagent (Thermo Fisher Scientific Inc.) according to the manufacturer’s instructions.…”

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

“…The reactivation of herpes simplex virus 1 (HSV-1) can lead to cranial nerve disorders and severe pain. Zhang et al revealed that HSV-1 disrupts the expression of T-type Ca 2+ channels in differentiated sensory-like neurons, as a means to disrupt pain responses [68,69]. Proteomics and transcriptomics showed that HSV-1 decreased the expression of the Ca V 3.2 T-type Ca 2+ channel subunit at the protein level, despite increasing Ca V 3.2 mRNA synthesis.…”