Size, site, and signaling: Three attributes of estrogen receptors

Estrogens are implicated in a diverse range of functions varying from reproduction, circulation, skeletal health to neuroprotection. Estrogens are also being increasingly recognized for their pathological contribution to cancers of various organs. This has spurred several investigations on estrogen-initiated signaling mechanisms in various cell types in physiological and pathological conditions. Estrogens exert their biological actions through a class of conventional nuclear receptors known as estrogen receptors (ERs), majorly of two subtypes – ERα and ERβ, both encoded by different genes, and each has multiple isoforms. It is reported that different ER subtypes and their specific isoforms have overlapping and nonoverlapping functions. Moreover, ER functions are highly cell-context specific. Thus, it is difficult to propose a unified scheme for estrogen signaling. Another layer of complexity is added by diverse subcellular localization, i.e., nucleus, plasma membrane, and cytosol, of ERs in estrogen-responsive tissues. Size as well as site dictates the sequence of cellular events triggered by estrogen signaling. This review compiles the existing information on different subtypes, different isoforms, and different sites of subcellular localization of ERs.