Dexmedetomidine Modulates Histamine-induced Ca²⁺Signaling and Pro-inflammatory Cytokine Expression

Abstract

Dexmedetomidine is a sedative and analgesic agent that exerts its effects by selectively agonizing α2 adrenoceptor. Histamine is a pathophysiological amine that activates G protein-coupled receptors, to induce Ca2+ release and subsequent mediate or progress inflammation. Dexmedetomidine has been reported to exert inhibitory effect on inflammation both in vitro and in vivo studies. However, it is unclear that dexmedetomidine modulates histamine-induced signaling and pro-inflammatory cytokine expression. This study was carried out to assess how dexmedetomidine modulates histamine-induced Ca2+ signaling and regulates the expression of pro-inflammatory cytokine genes encoding interleukin (IL)-6 and -8. To elucidate the regulatory role of dexmedetomidine on histamine signaling, HeLa cells and human salivary gland cells which are endogenously expressed histamine 1 receptor were used. Dexmedetomidine itself did not trigger Ca2+ peak or increase in the presence or absence of external Ca2+. When cells were stimulated with histamine after pretreatment with various concentrations of dexmedetomidine, we observed inhibited histamine-induced [Ca2+]i signal in both cell types. Histamine stimulated IL-6 mRNA expression not IL-8 mRNA within 2 hrs, however this effect was attenuated by dexmedetomidine. Collectively, these findings suggest that dexmedetomidine modulates histamine-induced Ca2+ signaling and IL-6 expression and will be useful for understanding the antagonistic properties of dexmedetomidine on histamine-induced signaling beyond its sedative effect.

The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels

“…reported that DEX treatment reduced the Ca 2+ response in astrocytes. In addition, the results of a recent study indicated that DEX treatment decreased histamine-induced Ca 2+ signaling in cancer cell lines31.…”

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

“…33 Another study reported that DEX modulated histamine-induced Ca 2+ signaling in cancer cell lines. 34 Based on our current findings, this is the first study to demonstrate that pretreatment with DEX protects H9c2 cardiomyocytes against OGD/R-induced injury by inhibiting [Ca 2+ ]i overload and caspase-3 dependent apoptosis through a direct regulation of the FKBP12.6/ RyR2 signaling (Figure 8). Studies showed that RyR2 dysfunction resulted in [Ca 2+ ]i overload during myocardial I/R injury.…”

Oxysterol-binding protein-related protein 4L promotes cell proliferation by sustaining intracellular Ca2+ homeostasis in cervical carcinoma cell lines

“…The role of Ca 2 + in promoting cell proliferation and cell death has been well illustrated and modeled in cancer cells [ 27 ]. The function of ORP4L was explored by a Ca 2+ fluorometry assay of peak calcium elevation after stimulation with histamine [ 28 ] in C33A cells subjected to ORP4L knockdown or overexpression, in a buffer containing 1.5 mM CaCl 2 . ORP4L knockdown significantly reduced the peak amplitude as compared to the control (Figure 2A ), whereas ORP4L overexpression significantly enhanced this peak amplitude (Figure 2B ).…”