17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

Abstract

Qiao GF, Li BY, Lu YJ, Fu YL, Schild JH. 17␤-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats. Am J Physiol Cell Physiol 297: C654 -C664, 2009. First published July 1, 2009 doi:10.1152/ajpcell.00059.2009.-We recently identified a myelinated vagal afferent subpopulation (Ah type) far more prevalent in female than male rats and showed that this difference extends to functionally specific visceral sensory afferents, baroreceptors of the aortic arch. Excitability of myelinated Ah-type afferents is markedly reduced after ovariectomy (OVX). Here we tested the hypothesis that 17␤-estradiol can selectively restore excitability of these sex-specific vagal afferents. Acutely isolated vagal afferent neurons (VGN) from intact and OVX adult female rats were used with patch-clamp technique and current-clamp protocols to assess the effect of acute application of 17␤-estradiol on neuronal excitability. At over physiologically relevant 17␤-estradiol concentrations for rat (1-10 nM) excitability of myelinated Ah-type vagal afferents is restored to discharge frequencies comparable to those in intact females, albeit with some interesting differences related to burst and sustained patterns of neuronal discharge. Restoration of excitability occurs within 3 min of hormone application and is stereo specific, because 1,000 nM 17␣-estradiol fails to alter excitability. Furthermore, activation of G protein-coupled estrogen receptor GPR30 with highly selective agonist G-1 similarly restores excitability of Ah-type afferents. The effectiveness of 17␤-estradiol and G-1 is completely eliminated by application of high-affinity estrogen receptor ligand ICI-182,780. 17␤-Estradiol conjugated with BSA is ϳ70% as effective as 17␤-estradiol alone in restoring Ah-type VGN excitability. These data support our conclusions that the cellular mechanisms leading to rapid restoration of neuronal excitability of myelinated Ah-type VGN after OVX occur, at least in part, via membrane-bound estrogen receptors. We contend that recovery of high-frequency discharge at physiologically relevant 17␤-estradiol concentrations implies that this unique subtype of low-threshold myelinated vagal afferent may account for some of the sex-related differences in visceral organ system function. Sex differences in cardiovascular and gastrointestinal function and the potential role of GPR30 in modulation of sex-specific myelinated Ah-type vagal afferents are discussed. sensory afferent; visceral afferent; estrogen receptor; GPR30; ovariectomy VISCERAL AFFERENTS with cell bodies in the vagal ganglia innervate a functionally diverse range of organs associated with the cardiovascular, gastrointestinal, and pulmonary systems. Vagal afferent mediation of the reflexogenic properties of the autonomic nervous system (ANS) in addition to visceral sensation is well recognized (for review see Ref. 55). Because the peripheral sensory terminals can be influenced by a wide range of endogenous chemicals released as a consequenc...

Sex differences in the physiology of eating

“…Thus, estrogen signaling apparently either 1) increases transduction of CCK-1 receptor activation into a vagal afferent signal (hypothesis 1) or 2) modulates processing of this signal in the NTS or further downstream (hypothesis 2). The findings that female rats have ϳ50% more myelinated vagal afferent fibers than males due to the presence of a specific low-threshold fiber type and that the excitability of these fibers is estrogen-dependent (430,575) are consistent with hypothesis 1. On the other hand, the necessity of ER␣ expression in the NTS for the estrogenic modulation of CCK satiation (please see cmNTS) strongly supports hypothesis 2.…”

Potentiation of 17β-estradiol on neuroexcitability by HCN-mediated neuromodulation of fast-afterhyperpolarization and late-afterdepolarization in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons via GPR30 in female rats

“…1C), suggesting that non-genomic and potentiated action of 17β-E 2 on neuroexcitability is due to G-protein coupled receptor activation. Consistent with previous observation [12], the effects of 17β-E 2 were not observed in either myelinated A-type or unmyelinated C-type BRNs.To explore the underlying ion channel mechanisms of 17β-E 2 's potentiation on respective discharge, large conductance Ca 2+ -activated K + channel (KCa1.1) [13] and HCN1 [1] are the two major channels that control the neuroexcitability and that may also be involved somehow in the potentiation in the presence of 17β-E 2 . Even though the functional downregulation of KCa1.1 in OVX females is responsible at least in part for the decreased neuroexcitability in Ah-type afferents neurons (data not shown), AP waveform seems not significantly altered before and after 17β-E 2 , therefore, the involvement of KCa1.1 in 17β-E 2 -mediated potentiation is largely excluded.…”

“…1C), suggesting that non-genomic and potentiated action of 17β-E 2 on neuroexcitability is due to G-protein coupled receptor activation. Consistent with previous observation [12], the effects of 17β-E 2 were not observed in either myelinated A-type or unmyelinated C-type BRNs.…”

Sex- and afferent-specific differences in histamine receptor expression in vagal afferents of rats: A potential mechanism for sexual dimorphism in prevalence and severity of asthma

“…Other reports demonstrated that the activa-54 tion of H 3 R could inhibit neurogenic microvascular leak-55 age in guinea-pig airways by prejunctional inhibition of 56 neuropeptide release from airway vagal sensory nerves 57 (Ichinose et al, 1990) and protect the lung against 58 acetylcholine-and capsaicin-induced edema via a pre-59 junctional modulatory effect on the C-fibers (Delaunois 60 et al, 1995) (Kashiba et al, 1999) -Cardoso et al, 1993;Undem and 79 Weinreich, 1993;Jafri et al, 1997). 80 In our previous study, we surprisingly found that in 81 adult female SD rats, histamine could sensitize all types 82 of NGNs including a low-threshold and sex-specific 83 myelinated Ah-type neurons ) that exist 84 predominantly in adult female rats and rarely in adult male 85 rats (Li and Schild, 2007;Li et al, 2008;Qiao et al, 2009;86 Santa Cruz Chavez et al, 2014). In stark contrast, his-87 tamine only sensitizes unmyelinated C-type NGNs with-88 out any effects on myelinated A-type NGNs in adult 89 male SD rats , which is consistent with 90 the results from male species in other reports (Higashi 91 et al, 1982;Undem and Weinreich, 1993 (Li and Schild, 2007), three neuron subpopulations were Ah-type NGNs (Fig.…”

“…(Li et al, 2007(Li et al, , 2008Li and Schild, 2007;Qiao et al, 617 2009Qiao et al, 617 , 2013Han et al, 2014;Santa Cruz Chavez et al, 618 2014;He et al, 2015;Yan et al, 2015). This unique phe-619 notype has many of the non-overlapping electrophysio-620 logical properties (Li et al, 2007(Li et al, , 2008Li and Schild, 621 2007; Qiao et al, 2009Han et al, 2014;Liu 622 et al, 2015;Yan et al, 2015) and chemical sensitivities 623 (Li and Schild, 2007; for their excellent technique support in RT-PCR and western blot 664 and valuable inputs in data interpretations.…”