Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurohumoral agents modulate intestinal transport by interactions with cell membrane receptors. Intracellular second messenger systems implicated in mediation of membrane receptor regulation of cellular events include the phosphoinositide and adenylate cyclase systems. In this study we have investigated the effects of direct postreceptor activation of key components of these systems on intestinal water and electrolyte transport. Rabbit ileal segments (n = 35) were arterially perfused ex vivo with an oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing 14C-polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- in six experimental groups were calculated for three 20-minute periods: basal, drug infusion, and recovery. The control group had no drug infusion. Two phorbol esters--phorbol 12, 13-diacetate (PDA; 10(-5) mol), and phorbol 12, 13-dibutyrate (PDB; 10(-5) mol)--were used to activate protein kinase C, an important component of the phosphoinositide system. The inactive 4 alpha-phorbol 12, 13-didecanoate (PDD; 10(-5) mol) served as a drug-infused control. Forskolin at two doses (FOR; 10(-5) mol and 10(-6) mol) was used to activate adenylate cyclase. The control and PDD groups had no changes in the flux of water and electrolytes. Both PDA and PDB had proabsorptive effects, with the more lipophilic and potent phorbol ester (PDB) having a more pronounced, significant effect (p less than 0.05). FOR caused significant secretion of H2O, Na+, and Cl- in a dose-dependent fashion (p less than 0.05). These results indicate that direct protein kinase C activation causes a proabsorptive effect and that direct activation of adenylate cyclase causes a secretory effect in the isolated small bowel. The activation status of these second messenger systems has a major influence on the transport state of the intestine.
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PMID:Postreceptor mechanisms of small-bowel water and electrolyte transport. 254 96

Digital imaging microscopy using the calcium-sensitive indicator probe fura-2 was combined with a reverse hemolytic plaque assay (RHPA) for growth hormone (GH) secretion. This technique allows dynamic measurements of the cytosolic free calcium concentration ([Ca2+]i) in individual pituitary somatotropes. Stimulation by growth hormone-releasing factor (GRF) increases, whereas somatostatin (SRIF) reduces [Ca2+]i in this cell type. [Ca2+]i increased in somatotropes when the cellular content of adenosine 3',5'-cyclic monophosphate (cAMP) was elevated by 1) activating cellular adenylate cyclase with forskolin (5 microM) and 2) treatment with the cAMP-analogues dibutyryl-cAMP (1 mM) or 8-bromo-cAMP (5 mM). The forskolin-induced calcium rise was abolished in the absence of extracellular calcium. This indicates that cAMP increases the influx of calcium into the cytosol and thereby stimulates hormone release. When forskolin was given in combination with SRIF (10 nM), [Ca2+]i decreased to the same level reached with SRIF treatment alone, indicating a site of action distal to the generation of cAMP. Activating protein kinase C with the phorbol ester 12,13-phorbol dibutyrate (PDB; 100 nM) increased [Ca2+]i as well. Again, this effect was dependent on extracellular calcium and blocked when PDB and SRIF were applied simultaneously. Combined stimulation with GRF plus PDB did not augment the response of [Ca2+]i over GRF treatment alone.
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PMID:Cytosolic free calcium in normal somatotropes: effects of forskolin and phorbol ester. 256 52

The membrane electrical properties and resting ionic conductances of frog semitendinosus muscle fibres were studied in vitro at 25 degrees C with the two-micro-electrode cable technique, in the presence of an activator or inhibitor of protein kinase C (PKC) or in the presence of an activator of adenylate cyclase. The PKC activator, 4 beta-phorbol 12,13-dibutyrate (4 beta-PDB), reduced chloride conductance (GCl) at concentrations greater than 1 microM and did not affect potassium conductance (GK). At 150 microM, the maximum concentration of 4 beta-PDB tested, GCl was reduced by 42%. The "inactive" phorbol ester 4 alpha-phorbol 12,13-dibutyrate did not affect GCl or GK. The inhibitory effect of 4 beta-PDB on GCl was prevented by pretreatment of the muscle preparation with the PKC inhibitor staurosporine. The adenylate cyclase activator forskolin (1.5-8 microM) significantly increased the GK of the fibres, without affecting GCl. Thus, we conclude that frog skeletal muscle GCl, unlike rat muscle GCl, is relatively insensitive to activators of PKC. Moreover, in frog muscle, protein kinase A is a likely modulator of GK, but not GCl.
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PMID:Regulation of resting ionic conductances in frog skeletal muscle. 832 21

The complete three-dimensional sensory module structures of the Pr ground state of Synechocystis 6803 Cph1 and the unusual Pfr ground state of the bacteriophytochrome PaBphP (PDB codes 2VEA and 3C2W respectively) have now been solved, revealing an asymmetrical dumbbell form made up of a PAS (Period/ARNT/Singleminded)-GAF (cGMP phosphodiesterase/adenylate cyclase/FhlA) bidomain carrying the chromophore and the smaller PHY (phytochrome-specific) domain. The PHY domain is structurally related to the GAF family, but carries an unusual tongue-like structure which contacts the larger lobe to seal the chromophore pocket. In 2VEA, the tongue makes intimate contact with the helical N-terminus; both the N-terminus and the tongue structures are quite different in 3C2W. As expected, the structures reveal ZZZssa and ZZEssa chromophore conformations in 2VEA and 3C2W respectively, associated with tautomeric differences in several nearby tyrosine residues. Two salt bridges on opposite sides of the chromophore, as well as the associations of the C-ring propionates also differ. It is still unclear, however, which of these structural differences are associated with bacteriophytochromes compared with Cph1 and plant-type phytochromes, the unusual 3C2W Pfr ground state functionality compared with the Pr ground state or the Pr compared with Pfr photoisomerism. To access the latter unambiguously, both Pr and Pfr structures of the same molecule are required. New solid-phase NMR data for Cph1 in the Pr, Pfr and freeze-trapped intermediate states reveal unexpected changes in the chromophore during Pfr-->Pr photoconversion. These, together with our efforts to solve the three-dimensional structure of a complete phytochrome molecule are also described.
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PMID:Phytochrome three-dimensional structures and functions. 2029 48