The angiotensin II type 1 (AT1) receptor has a crucial role in load-induced cardiac hypertrophy. Here we show that the AT1 receptor can be activated by mechanical stress through an angiotensin-II-independent mechanism. Without the involvement of angiotensin II, mechanical stress not only activates extracellular-signal-regulated kinases and increases phosphoinositide production in vitro, but also induces cardiac hypertrophy in vivo. Mechanical stretch induces association of the AT1 receptor with Janus kinase 2, and translocation of G proteins into the cytosol. All of these events are inhibited by the AT1 receptor blocker candesartan. Thus, mechanical stress activates AT1 receptor independently of angiotensin II, and this activation can be inhibited by an inverse agonist of the AT1 receptor.

Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

The seven-spanning calcium-sensing receptor (CaSR) activates multiple G proteins including Gq and Gi, and thereby activates a variety of second messengers and inhibits parathyroid hormone (PTH) secretion. However, the exact signaling mechanisms underlying the functional activity of CaSR are not yet fully understood. The heterozygous inactivation of CaSR or its inhibition by antibody blocking results in either familial hypocalciuric hypercalcemia or acquired hypocalciuric hypercalcemia (AHH), respectively. Here, we report the identification of a unique CaSR autoantibody in an AHH patient. Paradoxically, we find that this autoantibody potentiates the Ca 2؉ /Gq-dependent accumulation of inositol phosphates by slightly shifting the dose dependence curve of the Ca 2؉ mediated activation of phosphatidylinositol turnover to the left, whereas it inhibits the Ca 2؉ /Gi-dependent phosphorylation of ERK1/2 in HEK293 cells stably expressing human CaSR. Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca 2؉ , increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects. Our observations thus indicate that a calcium-stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi. Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion. This is the first report of a disease-related autoantibody that functions as an allosteric modulator and maintains G proteincoupled receptors (GPCRs) in a unique active conformation with its agonist. We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.allosteric modulation ͉ disease ͉ functional selectivity ͉ G protein-coupled receptors ͉ multiple active conformations

Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor-␤ 1 (TGF-␤ 1 ) regulates PSC activation and proliferation in an autocrine manner. The intracellular signaling pathways of the regulation were examined in this study. Immunoprecipitation and immunocytochemistry revealed that Smad2, Smad3, and Smad4 were functionally expressed in PSCs. Adenovirus-mediated expression of Smad2, Smad3, or dominant-negative Smad2/3 did not alter TGF-␤ 1

Our results suggest that qualitative and quantitative changes of serum IgA are determined at the level of stem cells, and that BMT from normal donors can attenuate glomerular lesions in HIGA mice. This approach may offer a new avenue to study the pathogenesis of IgA nephropathy.

Our current hypothesis may explain the mechanisms that underlie TKI-induced thyroid disorders. By learning how various kinds of TKIs affect thyroid function, we may elucidate how the angiogenesis in thyroid is regulated both physiologically and pathologically.

It has been suggested previously (AbdAlla, S., Lother, H., and Quitterer, U. (2000) Nature 407, 94 -98) that the angiotensin II type 1 receptor (AT 1 R) and the bradykinin B2 receptor (B2R) form constitutive heterodimers. Furthermore they demonstrate that AT 1 R signaling significantly increases in the presence of the B2R. These findings suggest that heterodimerization and potentiation of AT 1 R signaling is a universal phenomenon that occurs as a natural consequence of simultaneous expression of the two receptors. Hence this potential interaction is of great pharmacological and biological interest that adds an additional layer of complexity to the understanding of the cross-talk between the renin-angiotensin and kallikrein-kinin systems. Given the remarkable significance of this finding, scientists from four independent research groups have set out to reproduce and further examine the potential AT 1 R/B2R interaction. We have investigated functional potentiation by the B2R of AT 1 R signaling in three different cell lines using multiple assays including phosphoinositide hydrolysis, ERK activation, ␤-arrestin recruitment, and receptor selection and amplification technology, and we have examined dimerization using bioluminescence resonance energy transfer and regulated secretion/aggregation technology. However, although both the AT 1 Rs and B2Rs were functional in our systems and the systems were fine tuned to detect small changes in receptor function, we failed to detect any functional modulation by or physical interaction between the two receptor proteins. In contrast to the previous observations, our data collectively suggest that AT 1 R/B2R heterodimerization does not occur as a natural consequence of their simultaneous expression in the same cell nor does the B2R influence the AT 1 R signaling.The angiotensin II type 1 (AT 1 ) 5 receptor belongs to the superfamily of the seven-transmembrane (7TM) or G proteincoupled receptors. The AT 1 R is a key regulator of blood pressure and body fluid homeostasis, and its importance in renal and cardiovascular pathophysiology is underscored by the widespread use of receptor blockers and inhibitors of the angiotensin-converting enzyme in clinical practice (1, 2). There is mounting evidence that the AT 1 R may form both homo-and heterodimers and that dimerization could be important for the receptor function (3-14). For example, it has been shown that the AT 1 R decreases G q coupling when the receptor interacts with either the MAS or the angiotensin II type 2 (AT 2 ) receptors (6, 10 -12). It has also been shown that the AT 1 R can form complexes with the ␤ 2 -adrenergic receptors and that it is possible to achieve dual receptor inhibition of AT 1 R and ␤ 2 -adrenergic receptor signaling using only a single receptor antagonist (9). The AT 1 R also co-immunoprecipitates with the Dopamine D1 and D3 receptor in tissue specimen obtained from WistarKyoto and spontaneously hypertensive rats (13, 15). Finally AbdAlla et al. (5,7,16) have shown in a number of studies that the AT 1...

Background: cAMP-induced phosphorylation of RhoA has been considered to inhibit RhoA signaling, causing cell rounding. Results: Knockdown of RhoGDI␣ blocks cAMP-induced cell rounding, and RhoGDI␣-WT expression but not RhoGDI␣-S174A expression recovers. Conclusion: Phosphorylation of RhoGDI␣ likely inhibits RhoA by stabilizing a active RhoA-RhoGDI␣ complex. Significance: This may underlie G s /cAMP-induced cross-talk with G q /G 13 /RhoA signaling.