ESTG-stimulated dissociation of GPER:heterotrimeric G-protein (s) complex

Stimulation of GPER through E2 binding activates nucleotide exchange on heterotrimeric G-protein and subsequent release of G alpha (s) and G beta-gamma subunits. G alpha (s) stimulates adenylate cyclase and activates PKA through elevated cAMP levels, while the G beta-gamma complex transactivates EGFR signaling by releasing HB-EGF in a matrix-metalloprotease dependent fashion (Filardo et al, 2007; Filardo et al, 2002; Kanda and Watanabe, 2003; Thomas et al, 2005, Filardo et al, 2000; Ding et al, 2009; reviewed in Gaudet et al, 2015; Alexander et al, 2017; Filardo, 2018). In breast cancer cell lines and human keratinocytes, E2-stimulation of GPER results in elevated cAMP levels downstream of G alpha (s) in a PKA dependent-fashion (Filardo et al, 2002; Kanda and Watanabe, 2003; Kanda and Watanabe, 2004). In contrast, in HEK, MDCK and CHO cell lines, no E2-dependent increase in cAMP was observed, and GPER was found to constitutively repress cAMP production in an AKAP5-dependent manner. The reasons for these differences are unclear (Broselid et al, 2014; Gonzalez de Valdivia et al, 2017).

通过E2结合激活GPER，可触发异源三聚体G蛋白上的核苷酸交换，进而释放Gα(s)和Gβ-γ亚基。Gα(s)通过提高cAMP水平刺激腺苷酸环化酶，并激活PKA；而Gβ-γ复合物通过释放HB-EGF以基质金属蛋白酶依赖性方式激活EGFR信号传导（参见Filardo等，2007；Filardo等，2002；Kanda和Watanabe，2003；Thomas等，2005，Filardo等，2000；Ding等，2009；Gaudet等综述，2015；Alexander等，2017；Filardo，2018）。在乳腺癌细胞系和人角质形成细胞中，GPER的E2刺激导致Gα(s)下游cAMP水平升高，这一过程依赖于PKA（参见Filardo等，2002；Kanda和Watanabe，2003；Kanda和Watanabe，2004）。相反，在HEK、MDCK和CHO细胞系中，未观察到E2依赖性的cAMP增加，并且发现GPER以AKAP5依赖性方式恒定地抑制cAMP的产生。这些差异的原因尚不明确（参见Broselid等，2014；Gonzalez de Valdivia等，2017）。