Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous system and the periphery as well. The flexible G-protein interface of muscarinic receptors allows them to interact with several G-proteins with various efficacy, potency, and kinetics. Agonists biased to the particular G-protein mediated pathway may result in selectivity among muscarinic subtypes and, due to the non-uniform expression of individual G-protein alpha subunits, possibly achieve tissue specificity. Here, we demonstrate that novel tetrahydropyridine-based agonists exert specific signalling profiles in coupling with individual G-protein α subunits. These signalling profiles profoundly differ from the reference agonist carbachol. Moreover, coupling with individual Gα induced by these novel agonists varies among subtypes of muscarinic receptors which may lead to subtype selectivity. Thus, the novel tetrahydropyridine-based agonist can contribute to the elucidation of the mechanism of pathway-specific activation of muscarinic receptors and serve as a starting point for the development of desired selective muscarinic agonists.

• MeSH
• agonisté muskarinových receptorů * farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• karbachol farmakologie   MeSH
• lidé MeSH
• proteiny vázající GTP - alfa-podjednotky metabolismus   genetika   MeSH
• proteiny vázající GTP metabolismus   MeSH
• pyridiny farmakologie   MeSH
• receptory muskarinové * metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté muskarinových receptorů * MeSH
• karbachol MeSH
• proteiny vázající GTP - alfa-podjednotky MeSH
• proteiny vázající GTP MeSH
• pyridiny MeSH
• receptory muskarinové * MeSH

Strains of the yeast Saccharomyces cerevisiae, deficient in either of its two G-proteins, in the Snf3 and Rgt2 sensors, in the Gpr1 receptor and in various hexokinases were tested for their ability to start the activation cascade with a metabolizable monosaccharide that leads eventually to activation of plasma membrane H(+)-ATPase. The acidification rate after addition of glucose to glucose-grown cells and of galactose to galactose-grown ones, and the rate of ATP hydrolysis by purified plasma membranes in both types of cells were studied. It appears unequivocally that phosphorylation of the monosaccharide is essential for the activation; the role of the Gpa2 protein (possibly in combination with the Gpr1 receptor) is very probable while the two sensors appear to play somewhat ambiguous roles - in the absence of both the activation was actually higher than in the parent strain. The Gpa1 G-protein is not involved in acidification but may function in ATPase activity where, in addition to the phosphorylation step, other factors can play a role. There appear to be alternative pathways leading to the ultimate activation of the H(+)-ATPase, not necessarily involving G-proteins.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• aktivace enzymů MeSH
• buněčná membrána metabolismus   MeSH
• frakcionace buněk MeSH
• galaktosa metabolismus   MeSH
• geny hub MeSH
• glukosa metabolismus   MeSH
• hexokinasa genetika   metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• membránové proteiny genetika   metabolismus   MeSH
• mutace MeSH
• proteiny přenášející monosacharidy genetika   metabolismus   MeSH
• proteiny vázající GTP - alfa-podjednotky Gq-G11 MeSH
• proteiny vázající GTP - alfa-podjednotky genetika   metabolismus   MeSH
• protonové ATPasy genetika   metabolismus   MeSH
• receptory spřažené s G-proteiny genetika   metabolismus   MeSH
• regulace genové exprese u hub * MeSH
• Saccharomyces cerevisiae - proteiny genetika   metabolismus   MeSH
• Saccharomyces cerevisiae genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfát MeSH
• galaktosa MeSH
• glukosa MeSH
• GPA1 protein, S cerevisiae MeSH Prohlížeč
• GPR1 protein, S cerevisiae MeSH Prohlížeč
• hexokinasa MeSH
• membránové proteiny MeSH
• proteiny přenášející monosacharidy MeSH
• proteiny vázající GTP - alfa-podjednotky Gq-G11 MeSH
• proteiny vázající GTP - alfa-podjednotky MeSH
• protonové ATPasy MeSH
• receptory spřažené s G-proteiny MeSH
• RGT2 protein, S cerevisiae MeSH Prohlížeč
• Saccharomyces cerevisiae - proteiny MeSH
• SNF3 protein, S cerevisiae MeSH Prohlížeč