Mitogenic signaling by Gq/11-coupled receptors

By binding to their cognate GPCRs, many potent mitogens such as neuropeptides, angiotensin II or lysophosphatidic acid stimulate cell proliferation via engaging the ERK/MAPK cascade. As mentioned before, agonists stimulating Gq/11-coupled receptors activate PLCb isoforms thereby activating PKCs and elevating [Ca2+]i. These two second messengers represent key molecules for coupling Gq/11 proteins to the ERK/MAPK cascade. In this work, by means of GnRH in gonadotropic aT3-1 cells and galanin or bradykinin in SCLC cells, different aspects of Gq/11-dependent mitogenic signaling pathways were revealed. Our findings together with previous reports underline the notion that signaling pathways emanating from Gq/11-coupled receptors are tightly regulated in a cell- and receptor-specific manner

An Aminoisoxazole‐Based Proto‐RNA

Abstract The RNA world hypothesis predicts that life started with the development of replicating and catalytically active RNA, which evolved in a process of molecular evolution to increasingly complex chemical structures. RNA is, however, so complex that it has most likely formed from a precursor (proto‐RNA) that was more easily accessible in a prebiotic world. Recently, 3‐aminoisoxazoles (IO3) were identified as building blocks that can form under prebiotic conditions and can rearrange to give the nucleoside cytidine (C). The present study shows that the constitutional isomer 5‐aminoisoxazole (IO5) can undergo the same reaction to give uridine (U). Both compounds (IO3 and IO5), if embedded in RNA, react selectively to C and U, which are the main pyrimidine nucleosides of the genetic system. Importantly, the stereochemical outcome of the IO5 reaction in RNA depends on the neighboring bases. If they are β‐configured RNA nucleosides, the reaction proceeds with high selectivity to give exclusively the β‐configured U RNA base (anomeric control)

A Unifying Concept for the Prebiotic Formation of RNA Pyrimidine Nucleosides

Abstract The question of how nucleosides might have formed as essential precursor molecules on the early Earth is one of the many challenges associated with the origin of life. In this context, the prebiotic synthesis of pyrimidine nucleosides is controversially discussed. For the pyrimidines, two at first glance contradictory prebiotically plausible reaction pathways have been proposed, based on either oxazole or isoxazole chemistry. This study shows that these two reaction sequences can be merged under prebiotically reasonable conditions, suggesting that both pathways could have co‐existed and possibly interacted. The key precursor 3‐aminoisoxazole was found to react with the key intermediate of the oxazole route (ribo‐2‐(methylthio)oxazoline), to form a ribo‐isoxazole‐oxazoline hybrid structure, which collapses upon reductive N−O bond cleavage to give the nucleoside cytidine. The data suggest that different, interacting prebiotically plausible chemical pathways may have created the key molecules of life on the early Earth