Testosterone induces hyporesponsiveness by interfering with IP3 receptors in guinea pig airway smooth muscle

Montaño, Luis M.; Flores‐Soto, Edgar; Díaz-Hernández, Verónica; Carbajal‐García, Abril; Campuzano-González, Elías; Ramírez-Salinas, G. Lizbeth; Velasco-Velázquez, Marco A.; Sommer, Bettina

doi:10.1016/j.mce.2017.12.010

Cited by 24 publications

(15 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, E2 elicited non-genomic vasoconstriction in mice, which led to the reduction of skin cooling action [23]. The non-genomic smooth muscle relaxing effect of T was proved in human coronary arteries [24], umbilical arteries [25,26], peripheral vasculature of rats [27] and even in the trachea of guinea pigs [28,29]. However, a comparative investigation of the non-genomic effect of sex hormones on pregnant uterine contractions has not been carried out yet.…”

Section: Discussionmentioning

confidence: 99%

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

et al. 2020

View full text Add to dashboard Cite

The non-genomic (prompt) actions of sex steroids on pregnant uterine contractility are not fully explored yet, the aim of our study was to clarify such effects of 17-β estradiol (E2), progesterone (P4) and testosterone (T) on late (22-day) pregnant uterine contractions together with the signaling pathways in rats in vitro. Methods: The uterine effects of sex steroids on KCl-stimulated contractions were examined in the presence of genomic pathway blocker actinomycin D and cycloheximide, sex hormone receptor antagonists (flutamide, fulvestrant, mifepristone) and also after removing the endometrium. The modifications in uterine G-protein activation and cAMP levels were also detected. Results: T and E2 both relaxed the uterine contractions in the concentration range of 10 −8-10 −3 M with an increase in the activated G-protein and cAMP levels of the uterus, while P4 was ineffective. Cycloheximide, actinomycin D, antagonist for T and E2 were not able to modify the responses along with the endothelium removal. Mifepristone blocked the relaxing effects of T and E2 and reduced the activation of G-protein and the formation of cAMP. Significance: T and E2 can inhibit KCl-stimulated contractions in the late pregnant uterus in high concentrations and in a non-genomic manner. Their actions are mediated by a G-protein coupled receptor that can be blocked by mifepristone. A single and high dose of T or E2 might be considered in premature contractions, however, further preclinical and clinical studies are required for the approval of such a therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Testosterone elicits its action through AR both genomically and non-genomically [28, 59, 60]. Several studies have reported non-genomic efefcts of TES on ASM but have relied on animal models or cells derived from non-human species [17, 19, 26, 32]. There is no information on the expression profile of AR in human ASM, especially during inflammation, or on effects of long-term activation of AR on ASM in the context of [Ca 2+ ] i homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…The relaxant effects of androgen agonists on tracheal smooth muscle cells in animal models of asthma have been previously explored, with biological actions of TES and DHT shown to be mediated by the high-affinity androgen receptor (AR), a member of the nuclear receptor superfamily, which in response to hormone regulates gene expression in target tissues [28-31], including AR expression itself [28]. Studies in airway tissues from different animal species (especially guinea pig) find that AR activation modulates LTCCs and SOCC [25] as well as modulation of IP3 receptors [32], with effects being epithelium and potassium channel independent [33], and similar effects of Dehydroepiandrosterone (DHEA) in asthmatic guinea pig models [31]. In contrast, epithelium-dependent relaxation in rabbit trachea by TES has also been reported [26].…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells

Kalidhindi

Katragadda

Beauchamp

et al. 2019

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells. Methods: We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca2+ ([Ca2+]i) measured using Fluo-3 loaded real time [Ca2+]i imaging. Results: We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFα or IL-13-induced enhancement of ASM [Ca2+]i in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca2+ influx via L-type channels and store-operated Ca2+ entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66. Conclusion: Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca2+]i towards alleviating airway hyperresponsiveness.

show abstract

“…It has three isoforms (ITPR1, -2 and -3) derived from different genes, which share ~60-80% amino acid homology ( 120 , 121 ). These receptors have also been identified in different smooth muscles types, including ASM ( 36 , 122 - 124 ).…”

Section: Ryanodine and Ip 3 Receptorsmentioning

confidence: 98%

Maintenance of intracellular Ca2+ basal concentration in airway smooth muscle (Review)

et al. 2018

Self Cite

View full text Add to dashboard Cite

In airway smooth muscle, the intracellular basal Ca2+ concentration [b(Ca2+)i] must be tightly regulated by several mechanisms in order to maintain a proper airway patency. The b[Ca2+]i is efficiently regulated by sarcoplasmic reticulum Ca2+-ATPase 2b, plasma membrane Ca2+-ATPase 1 or 4 and by the Na+/Ca2+ exchanger. Membranal Ca2+ channels, including the L-type voltage dependent Ca2+ channel (L-VDCC), T-type voltage dependent Ca2+ channel (T-VDCC) and transient receptor potential canonical 3 (TRPC3), appear to be constitutively active under basal conditions via the action of different signaling pathways, and are responsible for Ca2+ influx to maintain b[Ca2+]i. The two types of voltage-dependent Ca2+ channels (L- and T-type) are modulated by phosphorylation processes mediated by mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinase 1 and 2 (ERK1/2). The MEK/ERK signaling pathway can be activated by G-protein-coupled receptors through the αq subunit when the endogenous ligand (i.e., acetylcholine, histamine, leukotrienes, etc.) is present under basal conditions. It may also be stimulated when receptor tyrosine kinases are occupied by the appropriate ligand (cytokines, growth factors, etc.). ERK1/2 phosphorylates L-VDCC on Ser496 of the β2 subunit and Ser1928 of the α1 subunit, decreasing or increasing the channel activity, respectively, and enabling it to switch between an open and closed state. T-VDCC is also probably phosphorylated by ERK1/2, although further research is required to identify the phosphorylation sites. TRPC3 is directly activated by diacylglycerol produced by phospholipase C (PLCβ or γ). Constitutive inositol 1,4,5-trisphosphate production induces the release of Ca2+ from the sarcoplasmic reticulum through inositol triphosphate receptor 1. This ion induces Ca2+-induced Ca2+ release through the ryanodine receptor 2 (designated as Ca2+ ‘sparks’). Therefore, several Ca2+ handling mechanisms are finely tuned to regulate basal intracellular Ca2+ concentrations. It is conceivable that alterations in any of these processes may render airway smooth muscle susceptible to develop hyperresponsiveness that is observed in ailments such as asthma.

show abstract

Testosterone induces hyporesponsiveness by interfering with IP3 receptors in guinea pig airway smooth muscle

Cited by 24 publications

References 49 publications

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells

Maintenance of intracellular Ca2+ basal concentration in airway smooth muscle (Review)

Contact Info

Product

Resources

About