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  • A putative SHBG receptor SHBG R has been postulated


    A putative SHBG GSK343 (SHBG-R) has been postulated for about thirty years [66], [69], [70]. The characterization of this receptor has been researched by several groups. There are different ideas on how this receptor works. On the one hand Fortunati et al. provide evidence that SHBG is already bound to an SHBG-R and E2 can bind to the SHBG-SHBG-R complex [71]; Rosner and coworkers suggested similarly that SHBG must first be bound by SHBG-R before the steroid is bound by SHBG [72]. These groups also agree that this receptor activates a signaling cascade that results in an increased level of cAMP inducing several effects in the cell [58], [60], [73], [74], [75]. Recent studies have a precise candidate for the SHBG-R. De Toni et al. showed that SHBG can bind to the GPRC6A – a member of the C family of GPRs [76]. GPRC6As are already known to bind osteocalcin, amino acids, and calcium [77], [78], [79], [80]. Interestingly, they also seem to be involved in steroid effects. GPCR6A null mice show severe illnesses that are correlated with steroids actions: osteopenia, feminization and metabolic syndrome [81]. 2010 Pi et al. provided evidence that GPRC6 can response to androgens and several other steroid hormones. Using testosterone-BSA-FITC constructs they show the binding of the steroid at the cell membrane also the activation of the receptor [82]. Implying De Toni’s results from 2016 it could also be possible that the effects that Pi described are mediated not only by binding of testosterone to GPCR6A but by binding the complex of SHBG and testosterone.
    How can we put this together? As described above the precise mechanisms of E2 working mechanism are not clear at all although we know a lot about them. All together we can summarize that there are two different kinds of mechanisms: a rapid response via membrane-associated actions and a response that takes hours to days and is mediated via genomic actions. The focus of E2 research has been laid on the rapid responses to steroids. As described above they seem to be mediated via membranous receptors like GPR30. Next to the obvious reactions like activation of MAPK-pathways or increase of secondary messenger levels, these membranous receptors or membrane-located receptors can also result in various effects including long time genomic effects. It would be therefore more useful not to distinguish according to the time that is needed (long term versus rapid response) but for the way of action (nuclear versus membrane-associated/located). Additionally it is to mention that there are other proteins that have a crucial influence on the function of estrogen action. PELP-1 for example is an estrogen action modulator and has been shown to be essential for the action of estrogen in mouse brain [83]. The genomic responses are known for quite a long time but there are still many questions about them. It is for example not clear yet the exact mechanism with which the steroid passes the membrane. The students are taught that due to their lipophilic character steroids can just pass the membrane via diffusion. Nevertheless researchers are not sure about this mechanism. It would be also likely that the steroid is captured within the bilayer and that there it needs a mechanism for the steroid to pass the membrane. As described above we can find different kind of E2 binding proteins that are located at the cytoplasmic side of the membrane. Especially splicing variants of the nuclear ERs could GSK343 work like a magnet and pull the steroids out of their membranous prison. Another facilitator in trafficking the steroid through the membrane could be a receptor for SHBG. The complex of E2 and SHBG binds in the periphery to the membranous receptor. Via internalization of the E2-SHBG-SHBGR complex the steroid reaches the cytoplasm in vesicles. Then, the complex is dissolved and the free E2 can bind to the cytoplasmic ERs as it has been described above [84].