Drugs online research references
J Biol Chem. 1994 Aug 26;269(34):21519-25.
Synthetic peptides as probes for G protein function. Carboxyl-terminal G alpha s peptides mimic Gs and evoke high affinity agonist binding to beta-adrenergic receptors.
Rasenick MM, Watanabe M, Lazarevic MB, Hatta S, Hamm HE.
Department of Physiology and Biophysics, University of Illinois College of Medicine at Chicago 60612-7342.
The molecular interfaces between Gs and the beta-adrenergic receptor were investigated using synthetic peptides corresponding to various regions of its alpha subunit, alpha s. These experiments were carried out on saponin-permeable C6 glioma cells in which the beta-adrenergic receptor appears tightly coupled to Gs. Synthetic site-specific peptides from alpha s (corresponding to amino acids 15-29, 354-372, and 384-394) and alpha i (8-22, 315-324, and 345-455) were tested for their ability to interfere with coupling between the beta-adrenergic receptor and Gs. The two carboxyl-terminal peptides from alpha s blocked beta-adrenergic stimulation of adenylyl cyclase in permeable cells. However, only alpha s-354-372 had this effect in C6 membranes. It is suggested that the partial uncoupling of Gs, which occurs subsequent to cell disruption, may be related to a change in the interaction of the alpha s carboxyl terminus with the beta-adrenoreceptor. Two carboxyl-terminal peptides, 354-372 and 384-394, could also mimic the effect of Gs to increase agonist affinity for the beta-adrenergic receptor. In combination, alpha s-354-372 and alpha s-384-394 increased the ability of isoproterenol to compete with 125I-pindolol binding in a partially additive manner. Synthetic peptides from alpha i and amino-terminal peptides from alpha s had no effect on beta-agonist binding, suggesting a high specificity of peptide effects. Two findings suggest that these peptides bind directly to the beta-adrenergic receptor and stabilize its high agonist affinity conformation. First, GTP and hydrolysis-resistant GTP analogs did not alter the high affinity binding in the presence of high concentrations of the peptides. Second, in S49 lymphoma cyc- cells, which lack Gs, these peptides evoked the high affinity agonist binding state of the beta-receptor. Neither peptide had an effect on antagonist binding affinity, as measured by propranolol displacement of 125I-pindolol. These data suggest that at least two regions on the alpha subunit of Gs participate in high affinity Gs binding to the beta-adrenergic receptor. The fact that these small peptides could mimic the holo-Gs effect on the receptor is rather surprising, and the specificity of the effect suggests that the primary and secondary structure of small regions of alpha s contain much of the information for specific interaction with beta-adrenergic receptors.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8063788&dopt=Abstract
J Physiol. 1994 May 15;477 ( Pt 1):149-59.
K+ shifts of skeletal muscle during stepwise bicycle exercise with and without beta-adrenoceptor blockade.
Hallen J, Gullestad L, Sejersted OM.
Department of Physiology, National Institute of Occupational Health, Oslo, Norway.
1. K+ efflux rate and control of K+ reuptake rate in exercising muscle cells was examined in six healthy female volunteers. 2. A K(+)-selective electrode in the femoral vein continuously monitored K+ concentration ([K+]fv) during bicycling. Power was increased stepwise 5-6 times by 30-40 W every fourth minute until exhaustion before and after I.V. administration of propranolol. Leg blood flow was measured by bolus injections of Cardiogreen. 3. [K+]fv increased from about 4.3 to 6.8 mmol l-1 at exhaustion both before and after propranolol administration, but after drug infusion endurance was reduced from 22.2 +/- 0.6 to 19.7 +/- 1.1 min, so [K+]fv rose more rapidly. 4. The exercise-induced efflux rate of K+ from the muscle cells was estimated to be about 11 mumol kg-1s-1 at exhaustion both before and after propranolol administration. 5. As an indicator of rate of net loss of K+ from the leg, veno-arterial concentration differences ([K+]fv-a) during first, fourth and fifth power increments were high after 15 and 40 s, but declined toward the end of each power step. Propranolol accentuated [K+]fv-a only after 15 and 40 s of the first and fourth increments. 6. The exercise-induced increase in reuptake rate of K+ in the muscle, estimated at exhaustion, was not significantly changed by propranolol and was about 10 mumol kg-1s-1, corresponding to about 15% of maximum Na(+)-K+ pump capacity in man. 7. Extracellular accumulation and loss of K+ from muscle during bicycle exercise is due to Na(+)-K+ pump lag. The higher [K+]fv during propranolol is mainly due to impaired redistribution outside the exercising muscles. In addition at low powers, beta-adrenoceptor blockade caused a transiently increased net loss due to an accentuated Na(+)-K+ pump lag.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8071881&dopt=Abstract
Br J Pharmacol. 1994 Jun;112(2):571-5.
Stimulation by menthol of Cl secretion via a Ca(2+)-dependent mechanism in canine airway epithelium.
Chiyotani A, Tamaoki J, Takeuchi S, Kondo M, Isono K, Konno K.
First Department of Medicine, Tokyo Women's Medical College, Japan.
1. To investigate the effect of menthol on airway epithelial ion transport function, we studied the bioelectrical properties of canine cultured tracheal epithelium by Ussing's short-circuit technique in vitro. 2. Addition of menthol (10(-3) M) to the mucosal but not the submucosal solution increased the short-circuit current (Isc) from 6.2 +/- 0.9 to 14.0 +/- 2.2 microA cm-2 (P < 0.001), and this effect was accompanied by increases in transepithelial potential difference and conductance. The response was dose-dependent, with the maximal increase from the baseline value and the concentration required to produce a half-maximal effect (EC50) being 6.4 +/- 0.9 microA cm-2 (P < 0.001) and 40 microM, respectively. 3. Other cyclic alcohols, including menthone and cyclohexanol, had no effect on the electrical properties. 4. The menthol-induced increase in Isc was not altered by pretreatment of the cells with amiloride, indomethacin, or propranolol but was abolished by diphenylamine-2-carboxylate, furosemide or substitution of Cl with iodide in the medium. 5. Menthol (10(-3) M) increased cytosolic levels of free calcium ([Ca2+]i) from 98 +/- 12 to 340 +/- 49 nM (P < 0.01) in fura-2-loaded tracheal epithelium but did not affect the intracellular adenosine 3',5'-cyclic monophosphate content. 6. These results suggest that menthol stimulates Cl secretion across airway epithelium, probably through a Ca(2+)-dependent mechanism, and might thus influence mucociliary transport in the respiratory tract.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8075875&dopt=Abstract
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