Regulation of T-type Ca2+ channel expression by herpes simplex virus-1 infection in sensory-like ND7 cells

Abstract

Infection of sensory neurons by herpes simplex virus (HSV)-1 disrupts electrical excitability, altering pain sensory transmission. Because of their low threshold for activation, functional expression of T-type Ca2+ channels regulates various cell functions, including neuronal excitability and neuronal communication. In this study, we have tested the effect of HSV-1 infection on the functional expression of T-type Ca2+ channels in differentiated ND7-23 sensory-like neurons. Voltage-gated Ca2+ currents were measured using whole cell patch clamp recordings in differentiated ND7-23 neurons under various culture conditions. Differentiation of ND7-23 cells evokes a significant increase in T-type Ca2+ current densities. Increased T-type Ca2+ channel expression promotes the morphological differentiation of ND7-23 cells and triggers a rebound depolarization. HSV-1 infection of differentiated ND7-23 cells causes a significant loss of T-type Ca2+ channels from the membrane. HSV-1 evoked reduction in the functional expression of T-type Ca2+ channels is mediated by several factors, including decreased expression of Cav3.2 T-type Ca2+ channel subunits and disruption of endocytic transport. Decreased functional expression of T-type Ca2+ channels by HSV-1 infection requires protein synthesis and viral replication, but occurs independently of Egr-1 expression. These findings suggest that infection of neuron-like cells by HSV-1 causes a significant disruption in the expression of T-type Ca2+ channels, which can results in morphological and functional changes in electrical excitability.

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].…”

Alpha Herpesvirus Egress and Spread from Neurons Uses Constitutive Secretory Mechanisms Independent of Neuronal Firing Activity

“…These neuropathic symptoms are thought to be caused by altered electrophysiology of infected neurons. HSV is reported to alter neuron excitability by downregulating expression and cell-surface localization of voltage-gated and inward rectifying ion channels [4–9], yet PRV and some syncytial strains of HSV are also reported to induce synchronized spontaneous neuronal activity in vitro and in non-myelinated neurons in vivo [4–8]. Using PRV reverse genetics, the Enquist laboratory previously showed that two viral membrane proteins are required for elevated spontaneous activity of neurons in vitro and in vivo : 1) membrane glycoprotein gB is part of the core fusion complex that mediates membrane fusion during viral entry and cell-cell fusion leading to syncytia; 2) membrane protein US9 (together with glycoproteins gE and gI) is required for vesicular transport of PRV particles and glycoproteins into the axon of neurons.…”

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

“…There is a significant expression of Cav3.2 T‐type Ca 2+ channel subunits in differentiated ND7/23 cells, resulting in Ca 2+ currents that are sensitive to inhibition by low concentrations of nickel ions and NNC 55 0396 (Zhang et al . ).…”

“…As our previous work has shown, infection of differentiated ND7/23 cells with HSV‐1 causes over 80% reduction of T‐type Ca 2+ functional channels 24–48 h post‐infection (Zhang et al . ). Our present findings demonstrate that 24 h treatment with IL‐6 post‐HSV‐1 infection restores the functional expression of T‐type Ca 2+ channels to the membrane.…”