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Lecture presents information about basics of molecular pharmacology, area of basic research dealing with characterisation of hormonal receptors and their signalling cascades with the help of biochemical, pharmacological and cell physiology approaches. Main discoveries in this field will be analysed in more details from historical perspective.
Lectures - in Czech - Last update: Liberda Jiří, RNDr., Ph.D. (16.12.2009)
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Recommended literature General:
Česky: Základní a klinická farmakologie, Bertrand G. Katzung, vydalo H & H, 1992, další české zdroje budou ještě doplněny
Reviews in czech:
P. Svoboda: Charakterisace hormonálních receptorů s pomocí přímé vazebné studie Chemické Listy, 77, 258-276, 1983
P. Svoboda: Přenos hormonálního signálu přes plasmatickou membránu v knize Molekularni biologie, str. 201-216, CSVTS, 1984
P. Svoboda: Membránové receptory a přenos informace. Vesmir, 68, 71-74, 1989
Svoboda P.: Úloha GTP-vazebných proteinů v přenosu hormonálního signálu. Čs. Physiol. 43, 20-24, 1994
Svoboda P.: Alfred G. Gilman a Martin Rodbell - úloha GTP-vazebných proteinů v přenosu signálu do nitra buňky. Nobelova cena za fyziologii a lekarstvi 1994, Casopis lekaru ceskych 134, 415-417, 1995
Special literature in english:
Svoboda P., Svartengren J., Snochowski J., Houstek J. and Cannon B. High number of highaffinity binding sites for (-)-3H dihydroalprenolol on isolated hamster brown fat cells Eur. J. Biochem. 102, 203-210, 1979
Svoboda P. and Mosinger B. Catecholamines and the brain microsomal Na,K adenosine- triphosphatase I. Protection against lipoperoxidative damage. Biochem. Pharmacol. 30, 427-432, 19881
Svoboda P. and Mosinger B.Catecholamines and the brain microsomal Na,K-adenosine-triphosphatase II. The mechanism of action Biochem. Pharmacol. 30, 433-439, 1981
Svartengren J., Svoboda P. and Cannon B. Desensitization of beta-adrenergic responsiveness in vivo. Decreased coupling between receptors and adenylate cyclase in isolated brown-fat cells. Eur. J. Biochem. 128, 481-488, 1982
Svartengren J., Svoboda P., Drahota Z. and Cannon B. The molecular basis for adrenergic desensitization of in hamster brown adipose tissue: uncoupling of adenylate cyclase activation Comp. Biochem. Physiol. 78C, 159-170, 1984
Svoboda P., Amler E. and Teisinger J. Different sensitivity of ATP+Mg+Na (I) and Pi+Mg (II) dependent types of ouabain binding to phospholipase A2. J. Membrane Biol. 104, 211-221, 1988
Ransnas L., Svoboda P., Jasper J. and Insel P. Stimulation of beta-adrenergic receptors of S49 lymphoma cells redistributes the alpha subunit of the stimulatory G protein between cytosol and membranes Proc. Nat. Acad. Sci. USA 86, 7900-7903, 1989
Svoboda P., Kvapil P., Insel P.A. and Ransnas L.A. Plasma-membrane independent pool of the alpha subunit of the stimulatory guanine-nucleotide binding protein in a low-density membrane fraction of S49 lymphoma cells Eur. J. Biochem. 208, 693-698, 1992
Svoboda P., Unelius L., Cannon B. and Nedergaard J. Attenuation of Gs alpha coupling efficiency in brown adipose tissue plasma membranes from cold-acclimated hamsters Biochem. J. 295,655-661,1993
Milligan G., Svoboda P. and Brown Ch. Why are there so many adrenoceptor subtypes? Biochem. Pharmacol. 48, 1059-1071, 1994
Svoboda P., Mullaney I. and Milligan G. Agonist induced transfer of the alpha subunits of the guanine-nucleotide-binding regulatory proteins Gq and G11 and of muscarinic m1 acetylcholine receptors from plasma membranes to a light-vesicular membrane fraction. Eur. J. Biochem. 224, 455-462, 1994
Kvapil P., Novotný J., Svoboda P. and Ransnas. L. The short and long forms of the alpha subunit of the stimulatory guanine-nucleotide-binding protein are unequally redistributed during (-)-isoproterenol-mediated desensitization of intact S49 lymphoma cells. Eur. J. Biochem. 226, 193-199, 1994
Svoboda, P., Gun-Do Kim, Grassie, M.A., Eidne K.A. and Milligan G. Thyrotropin releasing hormone-induced subcellular redistribution and down-regulation of the guanine nucleotide binding protein G11 alpha. Analysis of differences in agonist regulation of co-expressed G11 alpha species variants. Mol. Pharmacol. 314, 761-768, 1996
Svoboda P., Unelius L., Dicker A., Cannon B., Milligan G. and Nedergaard, J. Cold-induced reduction in Gi alpha proteins in brown adipose tissue. Effects on the cellular hypersensitization to norepinephrine caused by pertussis toxin-treatment. Biochem. J. 314, 761-768, 1996
Mullaney I., Caulfield M.P., Svoboda P. and Milligan, G. Activation, cellular distribution and enhanced degradation of the G proteins Gq and G11 by endogenously expressed and transfected phospholipase C-coupled muscarinic m1 acetylcholine receptors. Progress in Brain Research (J. Klein and K. Loffelholz, eds.), pp. 181-187, Elsevier, 1996
Novotný, J. and Svoboda, P. (1988) The long (GsL) and short (GsS) variants of the stimulatory guanine-nucleotide-binding protein. Do they behave in an identical way? J. Mol. Endocrinol. 20, 163-173
Drmota, T., Novotný, J., Kim, G.-D., Eidne, K.A., Milligan, G. and Svoboda, P. (1988) Agonist-induced internalisation of the G protein G11alpha and thyrotropin-releasing hormone (TRH) receptors proceed on different time-scales. J. Biol. Chem. 273, 21699-21707
Bouřová, L., Novotný, J. and Svoboda, P. (1999) The decrease in the short variant of Gs alpha protein is associated with an increase of [3H]CGP12177 binding, [3H]ouabain binding and Na,K-ATPase activity in brown adipose tissue plasma membranes of cold-acclimated hamsters. J. Mol. Endocrinol. 22, 55-64
Drmota, T., Novotný, J., Gold, G.W., Svoboda, P. and Milligan, G. (1999) Visualisation of distinct patterns of subcellular redistribution of the thyrotropin-releasing hormone receptor and Gq/G11 induced by agonist stimulation. Biochem. J. 340, 529-538
Novotný, J., Krušek, J., Drmota, T. and Svoboda, P. (1999) Over-expression of G11? protein prevents desensitization of Ca2+ response to thyrotropin-releasing hormone. Life Sci. 65, 889-900
Last update: Šonská Alice, Mgr., Dr. (08.09.2008)
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ústní zkouška v rozsahu sylabu Last update: Liberda Jiří, RNDr., Ph.D. (26.04.2012)
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Lectures
The historical development of understanding of hormonal receptors (since Paul Ehrlich and John Newport Langley)
Discovery of adenylylcyclase and cAMP (Earl Sutherland) = the key stone of molecular endocrinology and pharmacology
Membrane receptors ? classification; ligand, agonist, antagonist, partial agonist, inverse agonist
Radioisotopes in medicine and biology, liquid scintillation, beta and gama counting, Bq, Ci, radioligand, specific radioactivity, chemical stability of the radioligand, radiochemical stability
Ligand binding studies of membrane receptors, specific radioligands, saturation binding isotherm, Scatchard plot, calculation of Bmax and Kd values, allosteric and co-operative models of receptor-ligand interactions, Hill coefficient; criteria of Pedro Cuatrecassas for identification of receptor with the specific radioligand binding site
Why there are so many receptors for the single hormone or neurotransmitter? Heterogeneity of G protein coupled receptors (GPCR), splicing variants of 7TM receptors
Trimeric GTP binding regulatory proteins (G-proteins), discovery of trimeric G proteins (Martin Rodbell and Alfred G. Gilman)
Classification of the five main families of trimeric G proteins
Phosphoplipases C, phospholipases A2, phosphodiesterases and secondary messengers
Desensitisation of hormone response, internalisation, recycling and down-regulation of GPCR; internalisation and down-regulation of trimeric G proteins, cross-talk phenomena, membrane domains (Neubig, R. R. (1994) Membrane organisation in G-protein mechanism. FASEB J. 8, 939-946), feed-back regulations, multiple signalling cascades initiated by the same hormone or neutrotransmitter.
Sodium plus potassium activated, magnesium dependent adenosine triphosphatase (Na,K-ATPase), sodium pump, [3H]ouabain as specific marker of plasma membranes
Subcellular fractionation by differential and density-gradient centrifugation; isolation of plasma membranes and other subcellular particles; plasma membrane markers and enzyme activities.
Last update: Šonská Alice, Mgr., Dr. (08.09.2008)
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