Splicing factor hnRNPH drives an oncogenic splicing switch in gliomasThis study reveals two alternative splicing events that contribute to the development of glioma. HnRNPH is shown to control production of a pro-survival splice variant of the death-domain adaptor protein IG20-MADD and the motility-enhancing isoform of the RON receptor tyrosine kinase.
Heroin remains a major drug of abuse and is preferred by addicts over morphine. Like morphine, heroin has high affinity and selectivity for -receptors, but its residual analgesia in exon 1 MOR-1 knockout mice that do not respond to morphine suggests a different mechanism of action. MOR-1 splice variants lacking exon 1 have been observed in mice, humans, and rats, raising the possibility that they might be responsible for the residual heroin and morphine-6-glucuronide (M6G) analgesia in the exon 1 knockout mice. To test this possibility, we disrupted exon 11 of MOR-1, which eliminates all of the variants that do not contain exon 1. Morphine and methadone analgesia in the exon 11 knockout mouse was normal, but the analgesic actions of heroin, M6G, and fentanyl were markedly diminished in the radiant heat tailflick and hot-plate assays. Similarly, the ability of M6G to inhibit gastrointestinal transit was greatly diminished in these exon 11 knockout mice, whereas the ability of morphine was unchanged. These findings identify receptors selectively involved with heroin and M6G actions and confirm the relevance of the exon 11-associated variants and raise important issues regarding the importance of atypical truncated G-protein-coupled receptors.knockout ͉ analgesia ͉ opiate receptor
Mu opioid receptors play an important role in mediating the actions of a class of opioids including morphine and heroin. Binding and pharmacological studies have proposed several mu opioid receptor subtypes: mu(1), mu(2), and morphine-6beta-glucuronide (M6G). The cloning of a mu opioid receptor, MOR-1, has provided an invaluable tool to explore pharmacological and physiological functions of mu opioid receptors at the molecular level. However, only one mu opioid receptor (Oprm) gene has been isolated. Alternative pre-mRNA splicing has been proposed as a molecular explanation for the existence of pharmacologically identified subtypes. In recent years, we have extensively investigated alternative splicing of the Oprm gene, particularly of the mouse Oprm gene. So far we have identified 25 splice variants from the mouse Oprm gene, which are controlled by two diverse promoters, eight splice variants from the rat Oprm gene, and 11 splice variants from the human Oprm gene. Diversity and complexity of the Oprm gene was further demonstrated by functional differences in agonist-induced G protein activation, adenylyl cyclase activity, and receptor internalization among carboxyl terminal variants. This review summarizes these recent results and provides a new perspective on understanding and exploring complex opioid actions in animals and humans.
Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.
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