μ-Opioids activate tyrosine kinase focal adhesion kinase and regulate cortical cytoskeleton proteins cortactin and vinculin in chick embryonic neurons

We have investigated the signal transduction pathway of the G-protein μ-opioid receptor upstream of phospholipase D (PLD) and protein kinase C-ϵ (PKC-ϵ) activation in postmitotic E6CH chick embryo cortical neurons. The μ-opioid receptor and PLD-PKC-ϵ functional coupling depends on upstream tyrosine kinase activation. We now report that the μ-opioid agonists specifically stimulated tyrosine phosphorylation and activation of the focal adhesion kinase (FAK) in a time-dependent manner. We also demonstrate that met-enkephalin, a μ-opioid agonist in E6CH cultures, significantly increases tyrosine phosphorylation of another Src kinase substrate, the cytoskeletal protein cortactin. Tyrosine phosphorylation of cortactin led to drastic changes in subcellular localization, an estimated 2-fold enrichment in the cytosol. Similarly, opioids stimulated a sustained tyrosine phosphorylation of vinculin, a protein enriched in focal adhesion sites. These data provide novel evidence that opioid receptor intracellular signaling engages the specific activation of tyrosine kinase FAK and regulates the neuronal cytoskeleton during central nervous system morphogenesis. J. Neurosci. Res. 50:391–401, 1997. © 1997 Wiley-Liss, Inc.     

Numbering of cloned P2 purinoceptors

Over the last 3 years (March, 1993 to June, 1996), DNA sequences have been isolated for some 40 proteins that act as P2 purinoceptors. This explosion in receptor subtypes for nucleotide signalling and rate of advance (1 new receptor per month) have caused problems with the classification of these recombinant purinoceptors. At the request of the research community in this field, a “Purinoceptor Update Newsheet” was compiled at University College London with the view to monitoring and opening for general discussion new findings on P2 purinoceptor cloning and rapidly disseminating this information to investigators in this field. The present paper explains the system of numbering of the two families of receptor subtypes as proposed by Abbracchio and Burnstock [(1994): Pharmacol Ther 64:445–475] (P2X_1-n and P2Y_1-n purinoceptors, as extended families of ligand-gated and G protein-coupled receptors), and the order in which these subtypes appear in “Newsheet” tables. © 1996 Wiley-Liss, Inc.     

The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies

Transient receptor potential (TRP) channels are one primary type of calcium (Ca²⁺) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors’ efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.     

Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases

Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.