Estrogen receptor-α mediates estradiol attenuation of ATP-induced Ca2+ signaling in mouse dorsal root ganglion neurons

Abstract

A mechanism underlying gender-related differences in pain perception may be estrogen modulation of nociceptive signaling in the peripheral nervous system. In rat, dorsal root ganglion (DRG) neurons express estrogen receptors (ERs) and estrogen rapidly attenuates ATP-induced Ca2+ signaling. To determine which estrogen receptor mediates rapid actions of estrogen, we showed ERalpha and ERbeta expression in DRG neurons from wild-type (WT) female mice by RT-PCR. To study whether ERalpha or ERbeta mediates this response, we compared estradiol action mediating Ca2+ signaling in DRG neurons from WT, ERalpha knockout (ERalphaKO), and ERbetaKO mice in vitro. ATP, an algesic agent, induced [Ca2+]i transients in 48% of small DRG neurons from WT mice. 17beta-Estradiol (E2) inhibited ATP-induced intracellular Ca2+ concentration ([Ca2+]i) with an IC50 of 27 nM. The effect of E2 was rapid (5-min exposure) and stereo specific; 17alpha-estradiol had no effect. E2 action was blocked by the ER antagonist ICI 182,780 (1 microM) in WT mouse. Estradiol coupled to bovine serum albumin (E-6-BSA), which does not penetrate the plasma membrane, had the same effect as E2 did, suggesting that a membrane-associated ER mediated the response. In DRG neurons from ERbetaKO mice, E2 attenuated the ATP-induced [Ca2+]i flux as it did in WT mice, but in DRG neurons from ERalphaKO mice, E2 failed to inhibit the ATP-induced [Ca2+]i increase. These results show that mouse DRG neurons express ERs and the rapid attenuation of ATP-induced [Ca2+]i signaling is mediated by membrane-associated ERalpha.

Membrane Estrogen Receptor-α Interactions with Metabotropic Glutamate Receptor 1a Modulate Female Sexual Receptivity in Rats

“…Another possibility is that estradiol may be acting through another of the estradiol-binding proteins: G-protein-coupled receptor 30 (GPR30) (Revankar et al, 2005) or ER-X (Toran-Allerand et al, 2002). The present study was based on our previous study that MOR internalization required ER␣, because internalization and reproduction was disrupted in ER␣ knock-out but not in ER␤ knock-out animals Abraham et al, 2004;Chaban and Micevych, 2005;Watermann et al, 2006). Moreover, the GPR30 agonist G1 microinjected into the ARH does not internalize MOR in the medial preoptic nucleus (our unpublished results).…”

Estrogenic influences in pain processing

“…These membrane ERs may be novel or classical ERs associated with the plasma membrane. The presence of classic estrogen receptors may explain some of the non-genomic actions of estrogens (Abraham et al, 2004;Chaban and Micevych, 2005) but a brain-specific estrogen receptor X has also been proposed (Toran-Allerand et al, 2002). In addition, the G-protein-coupled receptor GPR30 may also bind estrogen (Revankar et al, 2005;Thomas et al, 2005).…”

“…This enables the activation of non-genomic responses regionally, thereby avoiding the need for high estrogen concentrations systemically, concentrations that could cause severe adverse effects on non-neural tissue (Cornil et al, 2006). The regulation of lordosis behavior (Micevych and Mermelstein, 2008) and signaling in the dorsal root ganglion (Chaban and Micevych, 2005) are in the time range more compatible with non-classic mechanisms (Micevych and Dominguez, 2009).…”

“…The ER has been shown to be essential to estrogen-related changes in nociception (Chaban and Micevych, 2005;Evrard, 2006;Kuba et al, 2005) not only through genomic influences but most likely also in a non-genomic manner. Studies in the male quail have revealed that estradiol can modulate the response to a noxious heat stimulus very rapidly (within minutes) at the spinal level and that this effect depends on local conversion of androgens into estrogens in laminae I-II by aromatase (Evrard and Balthazart, 2004b;Evrard, 2006).…”

“…ER and ER are expressed in cells in the rat trigeminal ganglion (Bereiter et al, 2005) and dorsal root ganglia (DRG) and regulate sensory neuron survival during the development of the DRG in this species (Patrone et al, 1999). Estrogens profoundly increase the size of the receptive field of primary afferent nerve fibers in female rats (Bereiter and Barker, 1975;Kow and Pfaff, 1973) and rapidly attenuate nociceptive signaling in female mouse primary afferent neurons by an ER-dependent mechanism that is most likely non-genomic (Chaban et al, 2011;Chaban and Micevych, 2005). Prolonged exposure to estradiol in neuronal cultures from DRGs of female rats inhibits activation of the ion channel TRPV1, which is central to nociceptive transmission in the DRG (Xu et al, 2008) and cultured trigeminal ganglion cells from ovariectomized rats exhibit increased sensitivity to capsaicin (Diogenes et al, 2006).…”