Testosterone can mediate which of the following

Ethanol-mediated inhibition was slower and linear solid circles. The y-axis represents the fraction of the original maximum current. Subsequent addition of n m testosterone to the carbachol-treated oocytes no longer attenuated GIRK activity last solid bar. T, Testosterone; carb, carbachol. However, to confirm that testosterone was not simply suppressing all potassium currents in a nonspecific fashion, the constitutive potassium channel ROMK renal outer medullary potassium channel was overexpressed in Xenopus oocytes, and potassium currents were measured in the presence of ethanol or testosterone.

M2R expression was confirmed by Western blot Fig. Notably, testosterone concentrations higher than n m had no greater inhibitory effects on GIRK activity data not shown. Interestingly, the dose response for testosterone-mediated inhibition of GIRK activity was nearly identical to that of testosterone-triggered maturation of oocytes from the same batch on the same day, suggesting that testosterone may be regulating both processes via the same receptor Fig. The percent inhibition of GIRK activity is shown on the y-axis, with the testosterone concentrations shown on the x-axis.

The percent maturation of oocytes from the same batch on the same day are shown below the graph. All experiments for this figure were performed at least three times with similar results. Interestingly, R binds tightly to the Xenopus AR and is a potent promoter of Xenopus AR-mediated transcription; however, it is unable to promote Xenopus oocyte maturation, even at high concentrations 15 , Thus, R is thought to be a selective AR modulator that specifically activates genomic but not nongenomic AR-mediated signaling.

Reduction of AR expression by RNA interference abrogates MAPK activation and oocyte maturation triggered by low concentrations of testosterone, suggesting that the classical AR mediates nongenomic signaling under these conditions 12 , 15 , To determine whether the classical AR similarly regulates testosterone-mediated inhibition of GIRK activity, potassium currents were measured in oocytes where AR expression was reduced by RNA interference 15 , In accordance with maturation studies 15 , low concentrations of testosterone 50 n m were no longer sufficient to inhibit GIRK activity in oocytes with reduced AR expression when compared with mock-injected oocytes, whereas high concentrations of testosterone n m still suppressed GIRK activity Fig.

MNAR expression was unchanged in these oocytes. B, The oocytes from panel A were treated with the indicated concentrations of testosterone, and potassium flux was measured after 5 min. What other receptor might testosterone be utilizing at high concentrations? One possibility is that testosterone binds to and activates the classical PR under these conditions. In fact, the androgens testosterone, androstenedione, and R were all capable of binding to the Xenopus PR, although with dissociation constants K d s that were to fold higher than those for binding to the Xenopus AR Table 1.

Importantly, the K d for testosterone binding to the AR was 0. Perhaps at higher concentrations, testosterone can bind to and signal via the Xenopus PR.

As proof in principle that androgens can activate a signal via the Xenopus PR, the androgens testosterone and androstenedione were shown to indeed activate PR-mediated transcription, albeit at lower levels relative to progesterone Fig. Cells were treated with the indicated steroids at a concentration of n m for 12 h.

B, Progesterone is a good activator of AR-mediated transcription. Cells were treated with 10 n m DHT or 0. Of note, these levels represent the maximum stimulation by the indicated steroids.

Higher concentrations of steroid did not further increase transcriptional activity. The values for progesterone and testosterone represent direct binding with radiolabeled steroid, whereas the rest were derived from competition studies using the indicated unlabeled steroid competing with 1 n m radiolabeled progesterone for PR or testosterone for AR. Values from Ref. Given that progesterone binds equally well to both the Xenopus PR and AR, and promotes AR-mediated transcription, progesterone may likewise mediate nongenomic AR-mediated signals.

As mentioned, one of the conundrums of progesterone-mediated oocyte maturation is that the classical PR antagonist RU does not block progesterone-triggered maturation. Interestingly, the Xenopus PR contains a cysteine rather than glycine at residue Fig. In contrast, the Xenopus AR contains a glycine at the equivalent position , likely explaining why RU bound with high affinity to the AR Table 1. The PR contains a cysteine residue at position , which results in decreased affinity for RU In contrast, the AR contains a glycine residue at the equivalent position, which allows it to bind to RU with high affinity.

Oocytes were treated with either 0. Each bar represents the percent maturation as determined by observing germinal vesicle breakdown for 20 oocytes. The experiment was repeated twice with similar results.

C, Model for steroid-triggered maturation of Xenopus oocytes. In vitro , progesterone can bind with equally high affinities to both the PR and AR and therefore likely promotes oocyte maturation via both receptor thick lines. In addition, progesterone is metabolized by endogenous CYP17 to androstenedione, which may activate maturation via high-affinity binding to the AR or low-affinity binding thin dotted line to the PR.

In vivo , significant levels of progesterone are not produced in response to gonadotropin. Instead, testosterone is produced, which triggers maturation via the AR at low concentrations due to its high affinity; thick line and both the AR and PR at high concentrations due to additional low affinity binding to the PR; thin dotted lines.

Like progesterone, the progestin RU also bound to the AR, although with fold lower affinity relative to its binding to the PR. Importantly, despite its high affinity for the Xenopus PR, RU does not promote oocyte maturation, but still activates Xenopus PR-mediated transcription 8. Thus, similar to the effect seen with R on the Xenopus AR, RU appears to be a selective PR modulator that specifically activates genomic but not nongenomic PR-mediated signaling.

As mentioned, a big problem studying progesterone-mediated oocyte maturation in vitro is that traditional PR antagonists have minimal inhibitory effects. Our binding studies may explain this problem because no one ligand sufficiently blocks both the AR and the PR. To address this issue, we attempted to block progesterone-mediated maturation using the high-affinity AR ligand R and the high-affinity PR ligand RU as competitive antagonists. Addition of R and RU together only promoted a small amount of oocyte maturation Fig.

R slightly inhibited progesterone-mediated maturation, most likely due to specific blockade of progesterone and its metabolite, androstenedione, binding to the Xenopus AR. RU inhibited progesterone-mediated maturation slightly more than R, likely because of its ability to bind tightly to the PR but still moderately to the AR.

Notably, maturation could not be reduced to zero by the inhibitors, most likely due to the partial agonist qualities of R and RU, as well as the extended incubation times used for a maturation assay 16 h. We have then used this system to test and confirm the validity of the release of inhibition hypothesis regarding steroid-mediated maturation of Xenopus oocytes.

First, we confirmed that resting oocytes contained constitutive GIRK activity. Second, we demonstrated that testosterone, the physiological mediator of Xenopus oocyte maturation, attenuated resting GIRK activity in a dose-dependent fashion Fig.

Intracellular Hormone Receptors. Figure Upon hormone binding, the receptor dissociates from the heat shock protein and translocates to the nucleus. In the nucleus, the hormone-receptor complex binds to a DNA sequence called a hormone response element HRE , which triggers gene transcription and translation. The corresponding protein product can then mediate changes in cell function. Plasma Membrane Hormone Receptors.

Summary Hormones cause cellular changes by binding to receptors on target cells. Exercises A new antagonist molecule has been discovered that binds to and blocks plasma membrane receptors. What effect will this antagonist have on testosterone, a steroid hormone? It will block testosterone from binding to its receptor. It will block testosterone from activating cAMP signaling. It will increase testosterone-mediated signaling. It will not affect testosterone-mediated signaling. What effect will a cAMP inhibitor have on a peptide hormone-mediated signaling pathway?

It will prevent the hormone from binding its receptor. It will prevent activation of a G-protein. It will prevent activation of adenylate cyclase. It will prevent activation of protein kinases. Name two important functions of hormone receptors.

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