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  • Having demonstrated that Gq coupled mGluR a was necessary

    2024-07-10

    Having demonstrated that Gq-coupled mGluR1a was necessary for estradiol-induced enhancement of CREB phosphorylation, we hypothesized that activation of a separate G-protein signaling pathway could explain the effect of estradiol on L-type calcium channel signaling (Boulware et al., 2005). Indeed, inhibition of group II mGluRs, which couple to Gi/o GSK J4 to inhibit adenylyl cyclase, eliminated the effect of estradiol. Furthermore, activation of either ERα or ERβ triggered group II mGluR signaling (Fig. 1). This work demonstrated specific bidirectional effects of estradiol within the same system, wherein the magnitude of concurrent excitatory input will dictate the outcome of estradiol exposure. Since these initial studies, a greater appreciation has emerged for how estradiol can influence neuronal systems via interactions with group I mGluRs. For example, group I mGluRs can activate a variety of cellular responses, including the release of endogenous cannabinoids (Alger and Kim, 2011; Wilson and Nicoll, 2002). Estradiol has also been known to influence this system (Maccarrone et al., 2002; Scorticati et al., 2004), and these lines of evidence have recently converged. Specifically, it has been demonstrated that in female hippocampal neurons, ERα activates mGluR1a leading to endocannabinoid signaling, subsequently decreasing presynaptic GABA neurotransmission (Huang and Woolley, 2012; Tabatadze et al., 2015). This example illustrates the potential impact of ER/mGluR interaction and the importance of thoroughly understanding of the signaling mechanism.
    Estradiol activation of ER/mGluR signaling underlies sex differences in addiction
    The nucleus accumbens is a critical locus for ER/mGluR signaling in the context of addiction
    ER/mGluR signaling is regulated by caveolin proteins and palmitoylation Because of the vast implications of ER/mGluR association, it is important to understand what regulates their interaction. Such regulatory mechanisms are likely to be dynamic, allowing the coupling of these receptors in not only a sex-specific manner, but also a cell-specific manner. Cell culture experiments point to two regulatory mechanisms: interaction with caveolin proteins, and palmitoylation. First, caveolin proteins – structural membrane proteins – are required to traffic ERs to the plasma membrane where they can associate with mGluRs (Boulware et al., 2007; Razandi et al., 2002). The particular caveolin isoform (there are three) determines the character of the ER/mGluR pairing. That is, ERα with mGluR1a or mGluR5, or ERα or ERβ with mGluR2/3. In this way, caveolin creates functional microdomains within the membrane, clustering receptors with their effector proteins, and providing subcellular spatial tuning (see Fig. 1). In an attempt to better understand the involvement of caveolin in ER/mGluR-mediated enhancement of cocaine plasticity, and to bring our in vitro findings into an in vivo paradigm, we overexpressed Cav1 in neurons of the nucleus accumbens in ovariectomized rats (Fig. 2a) and measured differences in locomotor responses to cocaine (Fig. 2b). We used a dose of cocaine previously shown to not produce behavioral sensitization in ovariectomized rats without estradiol supplementation, and hypothesized that Cav1 overexpression would mimic the enhancement normally seen with estradiol. Indeed, Cav1 animals increased their locomotor responses from the first to last day of cocaine exposure, while control animals did not (Fig. 2b). This indicated that Cav1 overexpression facilitated cocaine-induced plasticity. A second source of regulation is palmitoylation – reversible post-translational lipidation. ERs must be palmitoylated in order to signal at the membrane. It is possible that neurons utilize a palmitoylation-depalmitoylation cycle to divert greater or fewer ERs to the plasma membrane, or even to integrate membrane and neuronal estradiol signaling. Future studies of membrane-associated ER regulation and signaling will need to consider the recent advances in knowledge of depalmitoylation and local palmitoylation cycles (Fukata et al., 2013, Fukata et al., 2015, Fukata et al., 2016; Yokoi et al., 2016). Because palmitoylation is a dynamic process, it is possible that there could be an activity-dependent component of ER palmitoylation state (Tabatadze et al., 2013). We are only just beginning to understand the extent of palmitoylation influence on signaling mechanisms that rely on membrane-tethering of otherwise soluble proteins, including ER/mGluR activity.