The tyrosine kinase inhibitor genistein directly inhibits GABAA receptors

doi:10.1016/S0169-328X(99)00061-3

Molecular Brain Research

Volume 67, Issue 1, 6 April 1999, Pages 177-183

https://doi.org/10.1016/S0169-328X(99)00061-3 Get rights and content

Abstract

The protein tyrosine kinase (PTK) inhibitor genistein has been widely used to examine potential effects of tyrosine phosphorylation on neurotransmitter function. We report here that genistein inhibits GABA_A receptors through a direct effect. Extracellular application of genistein and GABA reversibly inhibited GABA-activated currents recorded from HEK293 cells expressing rat α1β2γ2S or α1β2 receptors, even when genistein was preequilibrated in the intracellular solution. Daidzein, an analog of genistein that does not block PTK, also inhibited GABA-activated current. Coapplication of lavendustin A, a specific inhibitor of PTK, had no effect on the GABA response. Our results demonstrate that genistein has a direct inhibitory effect on GABA_A receptors that is not mediated via inhibition of tyrosine kinase.

Section snippets

Acknowledgements

This work was supported from a grant from the American Heart Association and by NIH grant ES07904. We thank Dr. Donald Carter for supplying the cell lines used in this study and Ms. Cathy Bell-Horner for her technical assistance.

References (16)

T. Akiyama et al.
Use and specificity of genistein as inhibitor of protein-tyrosine kinase
Methods Enzymol.
(1991)
C. Amico et al.
Involvement of phosphatase activities in the run-down of GABA_A receptor function in rat cerebellar granule cells in culture
Neuroscience
(1998)
B.J. Hamilton et al.
Stable expression of cloned rat GABA_A receptor subunits in a human kidney cell line
Neurosci. Lett.
(1993)
B.S. Jassar et al.
GABA_A receptor modulation by protein tyrosine kinase in the rat diagonal band of Broca
Brain Res.
(1997)
S.J. Moss et al.
Modulation of amino acid-gated ion channels by protein phosphorylation
Intl. Rev. Neurobiol.
(1996)
C.F. Valenzuela et al.
Tyrosine kinase phosphorylation of GABA_A receptors
Mol. Brain Res.
(1995)
M. Gyenes et al.
Phosphorylation factors control neurotransmitter and neuromodulator actions at the γ-aminobutyric acid type A receptor
Mol. Pharmacol.
(1994)
C.-Y. Hsu et al.
Kinetic analysis of the inhibition of the epidermal growth factor receptor tyrosine kinase by lavendustin A and its analogue
J. Biol. Chem.
(1991)

There are more references available in the full text version of this article.

Cited by (55)

Toward an understanding of the role of the exposome on fragile X phenotypes
2023, International Review of Neurobiology
Fragile X syndrome (FXS) is the leading known monogenetic cause of autism with an estimated 21–50% of FXS individuals meeting autism diagnostic criteria. A critical gap in medical care for persons with autism is an understanding of how environmental exposures and gene–environment interactions affect disease outcomes. Our research indicates more severe neurological and metabolic outcomes (seizures, autism, increased body weight) in mouse and human models of autism spectrum disorders (ASD) as a function of diet. Thus, early-life exposure to chemicals in the diet could cause or exacerbate disease outcomes. Herein, we review the effects of potential dietary toxins, i.e., soy phytoestrogens, glyphosate, and polychlorinated biphenyls (PCB) in FXS and other autism models. The rationale is that potentially toxic chemicals in the diet, particularly infant formula, could contribute to the development and/or severity of ASD and that further study in this area has potential to improve ASD outcomes through dietary modification.
Medicinal Plants in Asia and Pacific for Parasitic Infections: Botany, Ethnopharmacology, Molecular Basis, and Future Prospect
2020, Medicinal Plants in Asia and Pacific for Parasitic Infections: Botany, Ethnopharmacology, Molecular Basis, and Future Prospect
Flavonoids as positive allosteric modulators of α7 nicotinic receptors
2019, Neuropharmacology
The use of positive allosteric modulators (PAM) of α7 nicotinic receptors is a promising therapy for neurodegenerative, inflammatory and cognitive disorders. Flavonoids are polyphenolic compounds showing neuroprotective, anti-inflammatory and pro-cognitive actions. Besides their well-known antioxidant activity, flavonoids trigger intracellular pathways and interact with receptors, including α7. To reveal how the beneficial actions of flavonoids are linked to α7 function, we evaluated the effects of three representative flavonoids -genistein, quercetin and the neoflavonoid 5,7-dihydroxy-4-phenylcoumarin- on whole-cell and single-channel currents. All flavonoids increase the maximal currents elicited by acetylcholine with minimal effects on desensitization and do not reactivate desensitized receptors, a behaviour consistent with type I PAMs. At the single-channel level, they increase the duration of the open state and produce activation in long-duration episodes with a rank order of efficacy of genistein > quercetin ≥ neoflavonoid. By using mutant and chimeric α7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The α7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of α7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.
Resting gamma power during the postnatal critical period for GABAergic system development is modulated by infant diet and sex
2019, International Journal of Psychophysiology
Citation Excerpt :
It appears more likely that these differences derive from interactions between compounds in soy-formula and developing GABAergic processes that could produce the observed set of circumstances wherein gamma power development is supported but the interaction of this development with cognitive functions is affected. Although there are no human data directly addressing these issues, there have been studies describing the postnatal development of GABAA receptors in primates (Hashimoto et al., 2009), and neuronal culture studies examining the effects of soy compounds on these receptors (Huang et al., 1999; Wan et al., 1997) that together may offer a plausible explanation for these results. Hashimoto et al. (2009) found that mRNAs encoding GABAA receptor subunits α1 and α2 in monkey prefrontal cortex followed different developmental trajectories—with α1 levels being lowest in neonates, increasing progressively during the early postnatal period, and continuing to increase during puberty and adulthood, and α2 levels showing the opposite pattern.
Gamma band activity (30–50 Hz) plays an essential role in brain development and function, but neither the early postnatal development nor subject and environmental factors influencing this development have been reported. We documented the development of resting gamma power using high density EEG recordings obtained each month from postnatal month 2 to 6 in 518 healthy infants who were breast-fed (170; 85 boys), fed milk formula (186; 97 boys), or fed soy formula (162; 90 boys). Gamma power was determined for 44 sites distributed over major brain regions and analyses were adjusted for background variables relevant to neurodevelopment. The results show gamma power follows a gradually increasing function across this time period that varies in topographic magnitude and is differentially influenced by subject and environmental variables—among which gestation, head circumference, and infant diet-sex interactions figure most prominently. Relationships between gamma power and standardized measures of infant behavioral development appear to be emerging but are in flux during this time. Since this postnatal period is considered critical in the development of the GABAergic system underlying the generation of gamma activity, the observed findings may reflect organizational changes that will influence the future development of gamma-related behavioral and neurocognitive functions.
Genistein alleviates anxiety-like behaviors in post-traumatic stress disorder model through enhancing serotonergic transmission in the amygdala
2017, Psychiatry Research
Citation Excerpt :
Independent of estrogenic effect, genistein can modulate various receptors and ion channels in the central nervous system through its inhibition of tyrosine kinase or via direct interaction with these receptors and ion channels. The potential targets of genistein include GABA (Huang et al., 1999), glycine (Zhu et al., 2003), serotonin, noradrenaline (Toyohira et al., 2010), Ca2+ channel (Yokoshiki et al., 1996), K+ and Na+ channels (Paillart et al., 1997), among which implication of serotonin in PTSD is well-documented. Numerous preclinical and clinical studies have implicated amygdala circuits in the modulation of anxiety responses.
Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder, characterized by intense fear, and increased arousal and avoidance of traumatic events. The current available treatments for PTSD have limited therapeutic value. Genistein, a natural isoflavone, modulates a variety of cell functions. In this study, we tested anti-anxiety activity and underlying mechanisms of genistein in a PTSD rat model. The rats were trained to associate a tone with foot shock delivery on day 0, then fear conditioning was performed on day 7, 14 and 21. Genistein (2–8 mg/kg) was injected intraperitoneally daily for 7 days. The anti-anxiety effects of genistein were measured by contextual freezing behavior and elevated plus maze. By the end of the experiments, the amygdala was extracted and subject to neurochemistry analysis. Genistein alleviated contextual freezing behavior and improved performance in elevated plus maze dose-dependently in PTSD rats. Furthermore, in these rats, genistein enhanced serotonergic transmission in the amygdala, including upregulation of tryptophan hydroxylase, serotonin, and phosphorylated (p)-CaMKII and p-CREB, as well. Genistein exerts anti-anxiety effects on a PTSD model probably through enhancing serotonergic system and CaMKII/CREB signaling pathway in the amygdala.
Is genistein neuroprotective in traumatic brain injury?
2015, Physiology and Behavior
The concerns about negative consequences of estrogen therapy have led to introduce other strategies to obtain estrogen's benefits in the brain. The present study tests the hypothesis that a major isoflavone of soy; genistein with estrogen-like activity can be neuroprotective in traumatic brain injury (TBI). The male Wistar rats were randomly divided to four groups: sham, TBI, vehicle and genistein. The TBI was induced by Marmarou method. The brain edema and the disruption of blood–brain-barrier (BBB) were evaluated 48 h post-TBI. Genistein (15 mg/kg) or dimethyl sulfoxide (DMSO) was injected i.p., twice after TBI. The intracranial pressure (ICP), the motor performance, and the beam-walk task (WB) were determined before trauma, on trauma day (D0), and first (D1) and second (D2) days post-TBI. Genistein inhibited a development of brain edema and a BBB permeability in TBI animals. An increase of ICP and a defect in motor and WB performance were showed following TBI, in all times evaluated. An increase of ICP induced by TBI was suppressed by genistein on D1 and D2 times. Genistein improved a motor disorder induced by TBI, on D1 and D2 times. Also an increase of traversal time in WB task was suppressed by genistein in TBI animals, on D1 and D2 times. The results of this study demonstrated that genistein can be neuroprotective in TBI. Genistein inhibited the disruption of BBB, the brain edema and the increase of ICP, and the disturbance of neurobehavioral performance in TBI.

View all citing articles on Scopus

View full text

Short communicationThe tyrosine kinase inhibitor genistein directly inhibits GABAA receptors

Abstract

Section snippets

Acknowledgements

Methods Enzymol.

Neuroscience

Neurosci. Lett.

Brain Res.

Intl. Rev. Neurobiol.

Mol. Brain Res.

Phosphorylation factors control neurotransmitter and neuromodulator actions at the γ-aminobutyric acid type A receptor

Mol. Pharmacol.

Kinetic analysis of the inhibition of the epidermal growth factor receptor tyrosine kinase by lavendustin A and its analogue

J. Biol. Chem.

Short communication
The tyrosine kinase inhibitor genistein directly inhibits GABA_A receptors