Role of estrogen receptor α in membrane-initiated signaling in neural cells: Interaction with IGF-1 receptor

Abstract

The mechanisms of action of estradiol in the nervous system involve nuclear-initiated steroid signaling and membrane-initiated steroid signaling. Estrogen receptors (ERs) are involved in both mechanisms. ERα interacts with the signaling of IGF-1 receptor in neural cells: ERα transcriptional activity is regulated by IGF-1 receptor signaling and estradiol regulates IGF-1 receptor signaling. The interaction between ERα and the IGF-1 receptor in the brain may occur at the plasma membrane of neurons and glial cells. Caveolin-1 may provide the scaffolding for the interaction of different membrane-associated molecules, including voltage-dependent anion channel, ERα and IGF-I receptor.

Introduction

The ovarian hormone estradiol, a key regulator of reproductive physiology, acts in different regions of the central nervous system to control neuroendocrine secretions, reproductive behaviors and non-reproductive events, modulating synaptic function and synaptic plasticity and affecting mood and cognition [1], [2], [3]. In addition, estradiol is a neuroprotective factor that promotes neuronal survival and tissue integrity in different experimental models of neurodegeneration [1], [4], [5]. As in other tissues, the actions of estradiol in the nervous system involve estrogen receptors (ERs) α and β [6], [7] and two different but interrelated mechanisms: (i) the transcriptional regulation of target genes, by nuclear-initiated steroid signaling, and (ii) rapid membrane and cytoplasmic actions, by membrane-initiated steroid signaling, which in turn may also finally result in the regulation of transcription [8], [9], [10]. ERs mediate nuclear-initiated estradiol signaling, acting as transcription factors that are activated after ligand binding to regulate the transcriptional activity of target genes. In addition, ERs are also involved in membrane-initiated steroid signaling [10], [11] and numerous actions of estradiol in the nervous system involve cross-talk between ERs and the membrane/cytoplasmic signaling of growth factor/neurotrophin receptors [12], [13].

Estradiol may directly interact with growth factors at different levels of the intracellular signaling pathways in neurons and glial cells, including the regulation of G proteins [14], [15], [16], [17], [18], the modulation of intracellular calcium levels [19], [20], [21], [22], [23], [24], [25], [26], [27], the activation of calcium-calmodulin-dependent protein kinase II [28], the activation of the src tyrosine kinase [18], [29], [30], the activation of extracellular signal-related protein kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade [12], [18], [21], [29], [31], [32], [33], [34], [35], [36], [37], the activation of the phosphatidylinositol 3-kinase (PI3K) pathway [32], [33], [37], [38], [39], [40], [41], the activation of c-jun-kinase [42], [43] and/or the phosphorylation of the cAMP response element binding protein (CREB) [44], [45], [46], [47], [48], [49], [50]. The colocalization of ERs with growth factor receptors in the same neural cells provides a cellular substrate for cross-coupling between these signaling pathways. For instance ERs colocalize with p75, the low-affinity NGF receptors, in cholinergic neurons of the basal forebrain [51]. In addition, there is a widespread colocalization of estrogen and neurotrophin receptors within estrogen and neurotrophin targets, including neurons of the cerebral cortex, sensory ganglia and PC12 cells [12], [52], [53], [54], [55]. Immunohistochemical analyses have also shown an abundant colocalization of ERs and insulin-like growth factor-1 (IGF-1) receptor in different neuronal and glial populations in the rat central nervous system [56], [57], [58].