It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

Diderot is widely praised as a master of lively, dramatic and original dialogue. This book studies the developing role of dialogue in his early writings (1745 to 1754). Diderot's earlier experiments with the dialogue form, meticulously charted and analysed by D. J. Adams, opened the way to the exploration of human communication and cooperation which lies at the heart of the Encyclopédie. At first for Diderot dialogue ended in the triumph of monologue, with one speaker reducing another to silence. But (...) one of his central problems was precisely that of solipsism. Is it possible for people to communicate effectively with each other? By engaging with this problem in his early writings Diderot gradually came to realise the epistemological importance of true dialogue as an escape from the solipsistic trap; and, slowly and hesitantly, he developed the form of communicative dialogue which was to flourish in the masterpieces of his later years. (shrink)

In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using mice, (...) and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. (shrink)