Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the β2-adrenoceptor

G-PROTEIN-COUPLED receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling1–3. But new evidence suggests a two-state model4–19 in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig. 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations7,8 and in vitro systems5,9–12,20–23. We have used a transgenic mouse model in which there is such marked myocardial overexpression of β2-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist24. We show that the β2-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

The molecular logic of endocannabinoid signalling

The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. © 2003, Nature Publishing Group. All rights reserved

Efficiency of UV Treatment with and without the photocatalyst titanium dioxide for the degradation of the cyanotoxin cylindrospermopsin

Cylindrospermopsin is a potent hepatotoxin, produced by several cyanobacteria including Cylindrospermopsis raciborskii, a species commonly found in water supplies in Queensland, Australia. This study focussed on an assessment of the effectiveness of ultra violet (UV) irradiation as a water treatment procedure for the degradation of cylindrospermopsin. Enhancement of UV treatment with the addition of the photocatalyst titanium dioxide was also examined. Results indicate that UV irradiation (>4750 μW cm) degrades cylindrospermopsin over an initial toxin concentration range of 50-350 μg L. In addition, there was an influence on the degradation rate from solution pH (4, 7 and 9), but less so from solution temperature (19, 28 and 35°C). Degradation was a first order kinetic relationship and the calculated half-life of cylindrospermopsin under UV irradiation (unbuffered, pH 6.5, 22 ± 2°C) was 14 ± 2 minutes. The addition of titanium dioxide (0.1 g L) to samples greatly increased the degradation rate to produce a calculated half-life of 2.8 ± 1 minutes