Sex hormone-binding globulin provides a novel entry pathway for estradiol and influences subsequent signaling in lymphocytes via membrane receptor

Abstract

The complex effects of estradiol on non-reproductive tissues/cells, including lymphoid tissues and immunocytes, have increasingly been explored. However, the role of sex hormone binding globulin (SHBG) in the regulation of these genomic and non-genomic actions of estradiol is controversial. Moreover, the expression of SHBG and its internalization by potential receptors, as well as the influence of SHBG on estradiol uptake and signaling in lymphocytes has remained unexplored. Here, we found that human and mouse T cells expressed SHBG intrinsically. In addition, B lymphoid cell lines as well as both primary B and T lymphocytes bound and internalized external SHBG, and the amount of plasma membrane-bound SHBG decreased in B cells of pregnant compared to non-pregnant women. As potential mediators of this process, SHBG receptor candidates expressed by lymphocytes were identified in silico, including estrogen receptor (ER) alpha. Furthermore, cell surface-bound SHBG was detected in close proximity to membrane ERs while highly colocalizing with lipid rafts. The SHBG-membrane ER interaction was found functional since SHBG promoted estradiol uptake by lymphocytes and subsequently influenced Erk1/2 phosphorylation. In conclusion, the SHBG-SHBG receptor-membrane ER complex participates in the rapid estradiol signaling in lymphocytes, and this pathway may be altered in B cells in pregnant women.

DMT alters cortical travelling waves

“…Previous electrophysiological studies investigating changes in spontaneous (resting state) brain function elicited by ayahuasca have reported consistent broadband decreases in oscillatory power ( Riba et al, 2002 ; Timmermann et al, 2019 ), while others have noted that the most marked decreases occur in α-band oscillations (8–12 Hz) ( Schenberg et al, 2015 ). Alpha decreases correlated inversely with the intensity of ayahuasca-induced visual hallucinations ( Valle et al, 2016 ) and are arguably the most reliable neurophysiological signature of the psychedelic state identified to-date ( Muthukumaraswamy et al, 2013 ) – with increased signal diversity or entropy being another particularly reliable biomarker ( Schartner et al, 2017 ).…”

“…Modern scientific research has mostly focused on intravenously injected DMT. Administered in this way, DMT’s subjective effects have a rapid onset, reaching peak intensity after about 2–5 min and subsiding thereafter, with negligible effects felt after about 30 min ( Strassman, 2001 ; Strassman, 1995a ; Timmermann et al, 2019 ).…”

“…Alpha decreases correlated inversely with the intensity of ayahuasca-induced visual hallucinations ( Valle et al, 2016 ) and are arguably the most reliable neurophysiological signature of the psychedelic state identified to-date ( Muthukumaraswamy et al, 2013 ) – with increased signal diversity or entropy being another particularly reliable biomarker ( Schartner et al, 2017 ). In the first EEG study of the effects of pure DMT on on-going brain activity, marked decrease in the α and β (13–30 Hz) band power was observed as well as increase in signal diversity ( Timmermann et al, 2019 ). Increase in lower frequency band power (δ = 0.5–4 Hz and θ = 4–7 Hz) also became evident when the signal was decomposed into its oscillatory component.…”

Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function

“…The process by which estrogens are transported throughout the body and exert their biologic effects in target tissues is not completely understood. The vast majority of synthesized estrogen circulates in the plasma bound to either serum albumin or sex hormone binding globulin (SHBG) (7,8). Only a small fraction (~1 to 2%) is unbound or "free" and available to bind to its receptors (9).…”

<p>Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogonadism In Metabolic Syndrome?</p>

“…It also displays a positive association with many components or consequences of MS and negative with SHBG and HDL, which suggests that inflammation plays an important role in the development of MS49 and is connected to insulin resistance 50–52. SHBG also affects inflammatory pathways by interacting with lymphocytes via membrane receptors 53. CRP shows no direct association with androgens, both gonadal and adrenal, implying that SHBG changes might happen prior to changes in androgens, suggesting even more the important role of early SHBG imbalance in MS. Our current and earlier research suggests that the consequence of chronic inflammation in patients with metabolic syndrome might be more complicated, affecting hormones and their carrier proteins as well 54…”