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Estrogen has multiple actions in the brain to modulate homeostasis, synaptic plasticity, neuroprotection and pain sensitivity. Previous studies have demonstrated that estradiol may affect the ion channel function. The role of voltage-gated sodium channels in the transmission of nociceptive and neuropathic pain messages is well-established. Herein, we report the effects of estradiol (E2) 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. We found that the extracellularly 17β-E2 inhibited TTX-S Na(+) currents and TTX-R Na(+) currents; the effects were rapid, reversible and in a concentration-dependent manner. Moreover, 17β-E2 did not significantly affect the activation curve for Na(+) channel, and shifted the steady-state inactivation curve for TTX-S and TTX-R Na(+) channels in the hyperpolarizing direction. We also found that the membrane impermeable E2-BSA was as efficacious as 17β-E2, whereas 17α-E2 had no effect. Blockers of PKC (GÖ-6983) and PKA (H-89) abrogated these acute effects of 17β-E2. In conclusion, E2 inhibited voltage-gated Na(+) channels in mouse DRG neurons through a membrane ER-activated PKC-PKA signaling pathway. Through the modulation of voltage-gated sodium currents, estradiol could affect cell excitability, firing properties.

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.

Parkinson's disease (PD) is a common neurodegenerative disorder with genetic risk factors. Semaphorin 5A (SEMA5A) was recognized as a risk factor for PD through high resolution whole genome association study by Maraganore et al. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to check two single nucleotide polymorphisms (SNPs) within SEMA5A in 340 PD patients and 222 PD free cases of Chinese Han ancestry and tested by gene sequencing. We found that the SEMA5A variant genotype (allele) of rs7702187 and rs3798097 had no association with the risk of PD in our sample. The AC haplotype was associated with a significant increased risk of PD and the AT haplotype showed an associated decreased risk of PD compared with the most common haplotype TC. Our findings suggested that haplotypes of SEMA5A may be involved in PD risk in the Chinese Han population.