Journal article: Journal of Pharmacology and Experimental Therapeutics

Evidence of the direct activation of Gq/11 and Gs G-proteins by agonist stimulation of the M2 muscarinic receptor.

Muscarinic M(2) receptors preferentially couple with the G(i/o) class of G-proteins to inhibit cAMP synthesis. However, they can also stimulate net synthesis of cAMP and inositol phosphate (IP) accumulation. We investigated in intact Chinese hamster ovary (CHO) cells expressing human M(2) receptors (CHO-M(2) cells) whether direct interaction of M(2) receptors with G(s) and G(q/11) G-proteins is responsible for the latter effects. Suppression of the G(s)alpha subunit using RNA interference abolished stimulation of cAMP synthesis induced by 1 mM carbachol in both control and pertussis toxin-treated CHO-M(2) cells but had no effect on the inhibition of forskolin-stimulated cAMP synthesis. Carbachol stimulated accumulation of IP with an EC(50) of 79 microM. Removal of the G(q),G(11), or both alpha subunits reduced this response by 78, 54, and 92%, respectively, whereas suppression of the G(s)alpha subunit had no effect. Similar results obtained in CHO cells expressing M(1) receptors that preferentially couple with G(s) and G(q/11) G-proteins confirmed the efficiency of siRNA treatments. Stimulation of M(2) receptors in control and pertussis toxin-treated cells by a series of full agonists with respect to inhibition of adenylyl cyclase displayed different efficacies in stimulating IP accumulation. Carbachol, acetylcholine, and oxotremorine-M [N,N,N-trimethyl-4-(2-oxo-1-pyrolidinyl)-2-butyn-1-ammonium] behaved as full agonists, furmethide (N,N,N-trimethyl-2-furanmethammonium) and methylfurmethide [(5-methyl-2-furyl)methyltrimethylammonium] were partial agonists, and oxotremorine (1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone) had no effect. Our results provide direct evidence of M(2) receptor coupling with the alpha subunits of G(s) and G(q/11) G-proteins and demonstrate induction of multiple receptor conformational states dependent on both the concentration and the nature of the agonist used.
Michal, P., El-Fakahany, E.E. and Doležal, V.: Muscarinic M2 receptors directly activate Gq/11 and Gs G-proteins. Journal of Pharmacology and Experimental Therapeutics 2007, 320, 607-14. IF=4,003

Author: dolezalbiomed.cas.cz

Review articles in prestige journal Nature Genetics
Identification of distribution and functional impact of DNA copy number variation in the rat

Review articles in prestige journal Nature Genetics
Identification of osteoglycin (Ogn) as a genetic determinant predisposing to left ventricular hypertrophy in rats, mice, and humans

Review articles in prestige journal Nature Genetics
Identification of single nucleotide polymorphisms and haplotype mapping in the rat

Review articles in prestige journal Nature Genetics
Identification of renal Cd36 as a genetic determinant of blood pressure and risk for hypertension

Journal article: Nature Genetics
Molecular-genetic basis of severe inherited mitochondrial disease – neonatal encephalo-cardiomyopathy.

Article: Obesity
Chemical derivatives of docosahexaenoic acid (DHA) in the prevention and reversal of obesity in mice fed a high-fat diet

Article: Diabetologia
n-3 fatty acids and rosiglitazone exerts additive effects on muscle glycogen synthesis in mice fed a high-fat diet

Journal article: Proceedings of National Academy of Sciences of the USA
Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task

Journal article: FASEB
In vivo content of mitochondrial ATP synthase is controlled by expression of the gene encoding hydrophobic subunit c.

Review article: Oncogene
Current informations about the FOXO subgroup of forkhead transcription factors and mechanism of regulation

Journal article: PLoS Computational Biology
Efficient coding principle confirmed for the sense of smell

Journal article: Neurobiology of Aging
Evidence of impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mouse model of Alzheimer´s disease.

Journal article: American Journal of Physiology Endocrinology and Metabolism
Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance

Journal article: Journal of Pineal Research
The role of proline residues in the structure and function of human MT2 receptor.

EBBS Award for Dr. Stuchlik
European Brain and Behaviour Society 40th Anniversary Award.

Gastroenterology
Insight into circadian clock within the rat colonic epithelial cells.

Review article: Genome Research
Identification of a direct linkage of mitochondrial genome variation to risk factors for type 2 diabates in conplastic strains

Journal of Biological Chemistry
N- terminal loop and wing W2- regions of forkhead domain are important for stability of the FoxO4-DBD-DNA complex.

Journal article: Journal of Pharmacology and Experimental Therapeutics
Evidence of prolonged agonistic action of wash-resistantly bound M1 selective agonist xanomeline at M2 and M4 muscarinic receptor.

Journal article: Proceedings of National Academy of Sciences of the USA
Impaired hippocampal rhythmogenesis in a mouse model of mesial temporal lobe epilepsy.

Journal article: Journal of Chromatography A
Study of posttranslational non-enzymatic modifications of collagen by CE–MS/MS, and HPLC–MS/MS