Differential effects of quercetin, a natural polyphenolic flavonoid, on L‐Type calcium current in pituitary tumor (GH₃) cells and neuronal NG108‐15 cells

Abstract

The effects of quercetin, a natural polyphenolic compound, on voltage-dependent L-type Ca(2+) current (I(Ca,L)) in rat pituitary GH(3) cells were investigated with the aid of the whole-cell voltage-camp technique. Quercetin (0.5-200 microM) stimulated I(Ca,L) in a concentration-dependent manner. The current-voltage (I-V) relationship of I(Ca,L) was slightly shifted to more negative potentials in the presence of quercetin. The EC(50) value of the quercetin-induced stimulation of I(Ca,L) was about 7 microM. The presence of quercetin (5 microM) shifted the steady state inactivation curve of I(Ca,L) to a more negative potential by approximately -10 mV. Although quercetin might increase intracellular cyclic AMP, sp-cAMPS did not affect I(Ca,L). In addition, neither flavone nor wortmannin had any effect on the amplitude of I(Ca,L), while epicatechin and genistein slightly suppressed it. Quercetin (50 microM) decreased the amplitude of tetrodotoxin-sensitive Na(+) current in GH(3) cells. Under current-clamp configuration, quercetin could increase the firing frequency of actions potentials. Conversely, in NG108-15 neuronal cells, quercetin suppressed the amplitude of I(Ca,L). The quercetin-induced inhibition of I(Ca,L) was abolished in NG108-15 cells preincubated with t-butyl hydroperoxide (1 mM). Quercetin-mediated stimulation of I(Ca,L) in GH(3) cells was presumably not associated with the level of intracellular cyclic AMP, or with the activity of tyrosine or phosphoinositide 3-kinases. Therefore, the effects of quercetin on ion currents may, at least in part, contribute to the underlying mechanisms through which it affects neuronal or neuroendocrine function.

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

“…pneumoniae -infected macrophages rescue the infection from persistence and results in a more productive infection, and similarly, our observations on applying nonspecific (verapamil) or L-type specific (isradipin) calcium channel blockers to infected epithelial cells support the view that these compounds activate rather than suppress the acute infection [11]. The impact of phenolic compounds on L-type channel mediated Ca 2+ influx varies depending on compound structure [49,50]. Of note, the phenolic compounds identified as the most potent antichlamydial compounds in the epithelial cell model [12] do not cluster together in this respect, as luteolin and octyl gallate, for instance, suppress Ca 2+ influx while quercetin and morin stimulate it.…”

Quercetin Targets Cysteine String Protein (CSPα) and Impairs Synaptic Transmission

“…Of note, CSPα has been suggested to be a Ca 2+ channel chaperone, but this notion has been controversial [32]–[38]. In addition, previous studies have concluded that quercetin is both an L type Ca 2+ channel activator [39] and inhibitor [40], [41] as well as a BKCa channel activator [42], Kir channel inhibitor [43] and Ca 2+ ATPase inhibitor [44], [45]. Although our data in Lymnaea VD4/LPeD1 respiratory neurons support the idea that quercetin's inhibition of CSPα activity leads to downstream inhibition of synaptic transmission, these findings together with the above stated reports could potentially also be explained by a direct block of presynaptic Ca 2+ channels by quercetin.…”

Mechanism of Myricetin Stimulation of Vascular L-type Ca2+Current

“…However, the observed, complete block of the current induced by the three well known L-type Ca 2ϩ channel blockers nifedipine, diltiazem, and verapamil in cells exposed to myricetin did not substantiate this hypothesis. Previous studies have shown how quercetin stimulates I Ca(L) in cells isolated from rat tail artery , in clonal rat pituitary GH 4 C 1 (Summanen et al, 2001), as well as GH 3 cells, but not in neuronal NG108 -15 cells (Wu et al, 2003). The electrophysiological characteristics of myricetin Ca 2ϩ channel agonism described here (degree of current enhancement, time for maximal effect development, stimulation of current-voltage relationship, stabilization of the inactivated state, lack of effects on I Ca(T) , modulation of voltage dependence, and kinetics of the current) are similar to those already observed with quercetin in the same experimental model .…”