Estradiol exerts an anti-apoptotic effect on a wide variety of tissues. Estradiol as classical steroid hormone diffuses through plasma membrane, activates ESR1 (membrane) and promotes its membrane localization [1]. Activation ESR1 (membrane) leads to anti-apoptosis [2], [3], [4].

Activated ESR1 (membrane) binds to and activates PI3K reg class IA (p85) [5], [6]. PI3K cat class IA via PtdIns(3,4,5)P3 and PDK (PDPK1) activates AKT(PKB) [7]. Upon Estradiol action, activated AKT(PKB) promotes anti-apoptosis.

Primarily, AKT(PKB) phosphorylates and activates eNOS which catalyzes the synthesis reaction of NO [5], [8]. NO promotes cell survival by several mechanisms, including inhibition of mitochondrial permeability transition pore opening [9].

AKT(PKB) directly phosphorylates and activates CREB1, which regulates transcription of Bcl-2 [10], [3]. [11]. Also, AKT(PKB) phosphorylates and inhibits BAD, thus preventing its binding and inhibition of Bcl-2 and Bcl-XL [12].

As a result of Estradiol action AKT(PKB) inhibits ASK1 (MAP3K5)/ MEK4(MAP2K4)/ JNK(MAPK8-10) cascade preventing inhibition of Bcl-2 and Bcl-XL [13], [14], [15].

Activation of Bcl-2 and Bcl-XL and suppression of Bax under Estradiol action prevents formation of mitochondrial permeability transition pore, release of Cytochrome c from the mitochondria into the cytoplasm, and activation of caspase cascade [12], [16].

Estradiol can also activate Protein kinases C (PKC) (e.g., PKC-epsilon and/or PKC-alpha) [17], [18]. This may be realized via PtdIns(3,4,5)P3 [19] and PDK (PDPK1) [20], [21]. PKC-epsilon and/or PKC-alpha phosphorylates voltage-dependent L-type Ca(II) channel, alpha 1C subunit and promotes Ca('2+) transport into the cytosol [17], [22]. Intracellular Ca('2+) rise activates Ca-dependent conventional forms of PKC, possibly PKC-alpha, which activates c-Src/ c-Raf-1/ MEK1(MAP2K1) and MEK2(MAP2K2)/ ERK1/2 pathway [23], [24], [25]. Activated ERK1/2 phosphorylates and activates p90RSK1 [26], [27], which activates CREB1, and that in turn promotes transcription of anti-apoptotic protein Bcl-2 [12], [22], [28]. PKC-epsilon activated by Estradiol action also can directly bind to Bax and inhibit its translocation into mitochondria [29].

ESR1 (membrane) also can directly or through G-proteins signaling activate c-Src, which further leads to ERK1/2 and p90RSK1 p90RSK1 activation. Activated p90RSK1 directly inhibits BCL2-antagonist of cell death (BAD) [26], [27].

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