Elsevier

Brain Research

Volume 1378, 10 March 2011, Pages 1-8
Brain Research

Research Report
Inhibition of voltage-gated sodium channels by bisphenol A in mouse dorsal root ganglion neurons

https://doi.org/10.1016/j.brainres.2011.01.022Get rights and content

Abstract

Bisphenol A (BPA), an estrogenic compound, is contained in cans, polycarbonate bottles, and some dental sealants. Exposure to BPA might have potential toxicological effects on the nervous system. Previous studies have demonstrated that BPA may affect ion channel function, but the effects of BPA on voltage-gated sodium channels are unknown. Herein, we report the effects of BPA on TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) Na+ currents, using a conventional whole-cell patch clamp technique from acutely isolated mouse dorsal root ganglion neurons. BPA inhibited TTX-S Na+ currents and TTX-R Na+ currents, the effects of BPA were rapid, reversible and in a concentration-dependent manner. Moreover, BPA could shift the voltage-gated activation curve for TTX-S Na+ channel in the hyperpolarizing direction without changing that for TTX-R Na+ channel; shift the steady-state inactivation curve for TTX-S Na+ channel in the depolarizing direction without changing that for TTX-R Na+ channel; and lengthen the time course of recovery from inactivation for both TTX-S Na+ current and TTX-R Na+ current. We also found that PKC inhibitor GÖ-6983 and PKA inhibitor H-89 blocked the BPA-induced inhibition of Na+ currents. Considering its complex modulatory effects on voltage-gated sodium channels, BPA might have potential toxicological effects on the nervous system and lead to a change in excitability of nociceptive afferent fibers.

Research Highlights

► BPA inhibited voltage-gated TTX-S Na+ currents and TTX-R Na+ currents in mouse DRG neurons. ► The modulatory action of BPA may be predominately mediated by PKC and PKA.

Introduction

Bisphenol A (BPA), a monomer of a plastic used in many consumer products including bottles and dental composites and sealants, has been highlighted due to its endocrine disrupting actions on the human body, although there is no clear consensus on detrimental health effects of BPA. Previous studies have shown that BPA may affect the reproductive (Salian et al., 2009) and developmental function (Stump et al., 2010), carcinogenesis (Wetherill et al., 2005), metabolism (Hugo et al., 2008), and the immune system (Alizadeh et al., 2006). In addition, BPA is likely to alter the morphological and functional properties of neuronal cells in the nervous system. Exposure to BPA may interfere with synaptic remodeling (Hajszan and Leranth, 2010), and permanently alter nociceptive responses and pain in a sex-related and exposure-related manner (Aloisi et al., 2002).

It has been shown that BPA is known as an estrogenic compound composed of two phenol rings connected by a methyl bridge, resulting in a structure similar to 17β-estradiol (E2) (Wetherill et al., 2007). E2 and the synthetic estrogen BPA may activate intracellular signals by two pathways: genomic (Hall and Korach, 2002) or nongenomic activation (Watson et al., 2007). In genomic activation, they bind intracellular estrogen receptors (ERs) in the cytosol or nucleus, resulting in the control of gene expression. In the case of nongenomic activation, E2 and BPA activate intracellular signals through the ERs, which is a rapid biological response. Previous studies have demonstrated that BPA may affect ion channel function via a non-genomic mechanism. For example, BPA directly modulates the pharmacological properties of GABAA receptors (Choi et al., 2007); increases the activity of Maxi-K channels (Asano et al., 2010); and rapidly disrupts intracellular Ca2+ homeostasis (Alonso-Magdalena et al., 2005). Importantly, however, there are no data available regarding effects of BPA on the function of voltage-gated sodium channels.

Voltage-gated Na+ channels mediate a rapid and transient increase in Na+ permeability in response to changes in membrane potential, thereby contributing to the generation and conduction of action potentials that serve as sensory signals from the periphery to the spinal cord through the primary afferent neurons. So the sodium channels in sensory neurons are implicated in the development of inflammatory and neuropathic pain. The primary afferent neurons with their cell bodies in the dorsal root ganglion (DRG) express two classes of Na+ currents that can easily be separated pharmacologically on the basis of sensitivity to tetrodotoxin (TTX), one blocked by nanomolar TTX (TTX-S) and the other resistant to micromolar TTX (TTX-R) (Dib-Hajj et al., 2010). Studies of voltage-gated sodium currents indicated that Na+ channels may be modulated by protein kinase C (PKC) and protein kinase A (PKA) (Gold et al., 1998).

In the present study, we investigated the effects of BPA on dynamics of voltage-gated sodium channels in isolated mouse DRG neurons using whole-cell patch clamp recording. Also, the roles of PKC and PKA signal pathway were examined.

Section snippets

Effects of BPA on voltage-gated Na+ channels

The whole-cell patch clamp technique was used to measure voltage-gated Na+ channels current in dorsal root ganglion neurons and determine the effects of BPA on Na+ channels. The Na+ currents in DRG neurons were elicited by a series of + 10 mV voltage steps to potentials between −80 and + 40 mV from a holding potential of −80 mV for TTX-S Na+ currents (Fig. 1A) or −70 mV for TTX-R Na+ currents (Fig. 1D). As shown in Fig. 1A, D, the Na+ currents were inhibited by 40 μM BPA, and the inhibitory effect was

Discussion

Here we investigated, for the first time, the effects of BPA on voltage-gated sodium channels in mouse DRG neurons. We found that the extracellularly applied BPA inhibited TTX-S Na+ currents and TTX-R Na+ currents via PKC and PKA-dependent signaling pathway, the effects of BPA were rapid, reversible, and in a concentration-dependent manner. Moreover, several alterations in Na+ channel kinetics were also induced by BPA, which included (1) shifting the voltage-gated activation curve for TTX-S Na+

Experimental procedures

All experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and the study was approved by the local IACUC.

Acknowledgments

This work was supported by the National Science Foundation of China (30771831; 81072329).

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