Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asthma is associated with dysfunction of the beta-adrenergic receptor adenylyl cyclase signal transduction pathway. It has been argued that this results from receptor down-regulation by beta-agonist therapy. This study examined the relationship between nonspecific bronchial responsiveness (NSBR) to methacholine (Newcastle dosimeter method) and beta-adrenergic receptor density (Bmax) and affinity (%KH) in membranes from peripheral blood mononuclear leukocytes (MNL) in 12 male (27.3 +/- 1.7 yr old) and 14 female (31.4 +/- 1.7 yr old) drug-naive subjects with and without symptoms of mild intermittent wheezing. None had ever smoked or received any antiasthma medication. "Hyperresponsive" subjects were defined as those (n = 11) whose simplified slope of FEF50 (calculated as the percent fall in FEF50 divided by the dose of methacholine) was more than one SD above the mean for asymptomatic subjects. The log of the slope was reproducible (repeatability coefficient = 0.43) on two nonconsecutive days. Multiple regression analysis (overall R2 = 0.57) revealed negative relationships between the log of the slope and both Bmax (p = 0.016) and %KH (p = 0.011). Analysis of variance confirmed a lower mean (+/- SEM) value of %KH in "hyperresponsives" (45.7 +/- 5.5%) than in "normoresponsives" (60.4 +/- 4.1%, p = 0.04) with a similar trend for Bmax (hyperresponsives = 33.5 +/- 4.1 fmol/mg, normoresponsives = 45.9 +/- 7.1 fmol/mg, p = 0.18). These relationships between bronchial responsiveness, Bmax, and %KH cannot be explained by drug therapy, and they provide further evidence that there is an intrinsic impairment in the function of beta-adrenergic receptors on peripheral MNLs from subjects with high levels of nonspecific bronchial responsiveness.
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PMID:Relationship between nonspecific bronchial responsiveness to methacholine and peripheral mononuclear leukocyte beta-adrenergic receptor function in young drug-naive subjects. 132 48

The effects of 5-hydroxytryptamine (5-HT) on force of contraction (FC), action potential (AP) and calcium current (ICa) were studied in human right atrial and left ventricular heart muscle. 5-HT exerted a concentration-dependent increase in FC in multicellular atrial preparations; the EC50 was approximately 3 x 10(-7) mol/l. Maximal increases in FC (252 +/- 58% of control values; mean +/- SEM, n = 6) were obtained at 5-HT 10(-5) mol/l. At this concentration, ICa was increased four- to sevenfold in enzymatically isolated atrial myocytes. In contrast, ventricular preparations did not respond to 5-HT; FC, AP and ICa remained unaffected. In the same preparations, FC was increased by isoprenaline three- to fourfold. These results confirm the observation that 5-HT induces a positive inotropic effect in the human atrium, possibly mediated by activation of the adenylyl cyclase - cyclic AMP system. Our study demonstrates, however, the complete lack of functional 5-HT receptors, with respect to changes in FC, in the human ventricle. Since the positive inotropic effect of 5-HT in the human heart is obviously restricted to the atrium, our findings question the concept of developing 5-HT receptor agonists for the treatment of heart failure.
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PMID:Positive inotropic response to 5-HT in human atrial but not in ventricular heart muscle. 133 23

Glucagon-stimulated adenylyl cyclase activity has been shown to change in liver membranes manipulated to alter either their fatty acid composition or fluidity. We examined whether membrane alterations induced by dietary manipulation affected receptor function. Glucagon- and beta-adrenergic-stimulated receptor-adenylyl cyclase systems were examined in liver membranes of rats fed diets containing 10% corn oil, 10% coconut oil (essential FFA deficient), or 8.5% coconut oil with 1.5% corn oil (essential FFA repleat). Basal and maximal nonreceptor-mediated adenylyl cyclase activity (stimulated by NaF, guanylylimidodiphosphate, and forskolin) was the same in membranes of each of the dietary groups, suggesting that Gs-protein and the catalytic unit activity per se were unaltered by the manipulations. Glucagon-stimulated adenylyl cyclase activity increased with increasing unsaturation of dietary fatty acids; activity in coconut oil-fed rats was 527 +/- 30 (mean +/- SEM) pmol/mg.10 min, that in coconut/corn oil-fed rats was 752 +/- 74 pmol/mg.10 min, and that in corn oil-fed rats was 981 +/- 94 pmol cAMP/mg.10 min. [125I]Monoiodoglucagon binding did not increase in parallel to the adenylyl cyclase alterations; coconut oil-fed animals (614 fmol/mg) differed from the other groups (450 and 430 fmol/mg). Isoproterenol (beta-adrenergic)-stimulated adenylyl cyclase activity was also highest in the corn oil-fed animals, but was similar in the other dietary groups, with no difference in other characteristics of [125I]iodopindolol binding between the groups. The results demonstrate that alterations in the glucagon-stimulated adenylyl cyclase response are different from those in the beta-adrenergic adenylyl cyclase response. Further, they suggest that although direct activations of the catalytic unit or its interaction with the guanine nucleotide-sensitive protein are apparently not affected, hormone receptor-mediated adenylyl cyclase activity may be altered by these dietary manipulations.
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PMID:Altered glucagon- and catecholamine hormone-sensitive adenylyl cyclase responsiveness in rat liver membranes induced by manipulation of dietary fatty acid intake. 222 11

In addition to conveying cellular responses to an effector molecule, receptors are often themselves regulated by their effectors. We have demonstrated that epinephrine modulates both the rate of transcription of the beta 2-adrenergic receptor (beta 2AR) gene and the steady-state level of beta 2AR mRNA in DDT1MF-2 cells. Short-term (30 min) exposure to epinephrine (100 nM) stimulates the rate of beta 2AR gene transcription, resulting in a 3- to 4-fold increase in steady-state beta 2AR mRNA levels. These effects are mimicked by 1 mM N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate (Bt2cAMP) or foskolin but not by phorbol esters. The half-life of the beta 2AR mRNA after addition of actinomycin D (46.7 +/- 10.2 min; mean +/- SEM; n = 5) remained unchanged after 30 min of epinephrine treatment (46.8 +/- 10.6 min; mean +/- SEM; n = 4), indicating that a change in transcription rate is the predominant factor responsible for the increase of beta 2AR mRNA. Whereas brief exposure to epinephrine or Bt2cAMP does not significantly affect the total number of cellular beta 2ARs (assessed by ligand binding), continued exposure results in a gradual decline in beta 2AR number to approximately 20% (epinephrine) or approximately 45% (Bt2cAMP) of the levels in control cells by 24 hr. Similar decreases in agonist-stimulated adenylyl cyclase activity are observed. This loss of receptors with prolonged agonist exposure is accompanied by a 50% reduction in beta 2AR mRNA. Transfection of the beta 2AR promoter region cloned onto a reporter gene (bacterial chloramphenicol acetyltransferase) allowed demonstration of a 2- to 4-fold induction of transcription by agents that elevate cAMP levels, such as forskolin or phosphodiesterase inhibitors. These results establish the presence of elements within the proximal promoter region of the beta 2AR gene responsible for the transcriptional enhancing activity of cAMP and demonstrate that beta 2AR gene expression is regulated by a type of feedback mechanism involving the second messenger cAMP.
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PMID:cAMP stimulates transcription of the beta 2-adrenergic receptor gene in response to short-term agonist exposure. 247 35

Superluteinized rats were injected with the prostaglandin F2 alpha (PGF2 alpha) analogue cloprostenol to induce luteolysis. The treatment decreased progesterone production of ovarian homogenates from 8.9 +/- 0.5 to 4.0 +/- 0.7 nmol/ovary/10 min (mean +/- SEM) within 40 min. tochondrial fractions isolated from control and cloprostenol treated animals produced 4.7 +/- 0.4 and 2.8 +/- 0.3 nmol progesterone/ovary/10 min, respectively. Thus, the PGF2 alpha analogue treatment significantly reduced mitochondrial progesterone production. Addition of the 15 000 X g supernatant fraction did not influence the progesterone production rates of the mitochondrial fraction. The basal progesterone secretion from quartered ovaries decreased from 1.50 +/- 0.15 to 0.38 +/- 0.05 nmol/ovary during the initial 15 min of incubation following cloprostenol administration. hCG and N6,O2'-dibutyryladenosine 3':5'-cyclic monophosphate (DBC) stimulated the progesterone secretion from quartered ovaries, but the response was delayed in ovaries obtained from cloprostenol treated animals. Although the response was delayed, the progesterone secretion following cloprostenol treatment was re-activated with cAMP either directly or via hCG. The increment in progesterone secretion above unstimulated controls in response to DBC was not influenced by the cloprostenol treatment while the increment caused by hCG was decreased. Our data suggest that: 1) PGF2 alpha deactivates mitochondrial progesterone production, 2) this deactivation may be overcome by cAMP, and 3) PGF2 alpha decreases gonadotrophin responsive adenylyl cyclase.
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PMID:Ovarian production of progesterone and 20 alpha-dihydroprogesterone in vitro following prostaglandin F2 alpha induced luteolysis in the superluteinized rat. 632 May 70

The possibility that pituitary adenylyl cyclase-activating peptide (PACAP) is an inhibitory neurotransmitter has been investigated in the taenia of the guinea-pig caecum. The action of PACAP on muscle contractility and its ability to alter levels of adenosine-3':5'-cyclic monophosphate (cyclic AMP) and guanosine-3':5'-cyclic monophosphate (cyclic GMP) were investigated. PACAP-1-27 was an effective agonist, giving relaxations comparable in magnitude to isoproterenol; its EC50 was 3.4 x 10(-7) M. PACAP (10(-6) M) caused an almost two-fold increase in cyclic AMP levels; but the level of cyclic GMP was not affected. The relaxation caused by PACAP was slow in onset, with a latency of 5.8 +/- 0.8 s and reached a maximum at 9.1 +/- 1.1 s after onset. The relaxation was significantly reduced by apamin (10(-6) M) and suramin (10(-4) M) but was not reduced by tetrodotoxin (10(-7) M). Relaxation of the taenia coli caused by electrical stimulation of the inhibitory nerves was greatly reduced by apamin but only slightly reduced by suramin. PACAP-like immunoreactivity (-IR) was localised immunohistochemically in varicose nerve fibres within the taenia coli and in the underlying myenteric plexus and circular muscle. Approx. 50% of vasoactive intestinal peptide (VIP)-IR nerve fibres in the taenia also had immunoreactivity for PACAP; conversely, almost all PACAP-IR fibres were immunoreactive for VIP. PACAP-IR and substance P (SP)-IR were generally in separate fibres; only about 5% of SP-IR fibres were PACAP-IR. Radioimmunoassay revealed tissue concentrations of PACAP-1-27 and PACAP-1-38 of 1.0 +/- 0.1 and 2.1 +/- 0.3 (SEM) pmol/g wet weight of tissue, respectively. Material with PACAP-1-27 immunoreactivity co-eluted with authentic PACAP-1-27 on gel filtration chromatography, and PACAP-1-38 immunoreactivity also co-eluted with the authentic peptide. This study provides structural, chemical and pharmacological evidence that PACAP could be involved in inhibitory neurotransmission to the taenia coli of the guinea-pig caecum.
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PMID:Histochemical, pharmacological, biochemical and chromatographic evidence that pituitary adenylyl cyclase activating peptide is involved in inhibitory neurotransmission in the taenia of the guinea-pig caecum. 771 25

Binding to PTH to its cell surface receptor activates both adenylyl cyclase and phospholipase-C, leading to elevation of cytosolic cAMP and free Ca2+. We have shown previously that extracellular nucleotides interact with P2U and P2Y subtypes of purinoceptor on osteoblastic cells, both linked to Ca2+ mobilization. In the present study, we investigated possible interactions between nucleotide and PTH signaling pathways in osteoblastic cells. The cytosolic free Ca2+ concentration ([Ca2+]i) of UMR-106 osteoblastic cells was monitored by fluorescence spectrophotometry. PTH (0.01-1 microM; bovine 1-84 or human 1-34) induced a small transient elevation of [Ca2+]i, lasting less than 1 min. A number of nucleotides, including ATP, UTP, and UDP, induced transient elevation of [Ca2+]i and potentiated the subsequent Ca2+ response to PTH. Of the nucleotides tested, UDP was the most effective at potentiating the PTH-induced Ca2+ transient. Treatment of cells with UDP (100 microM for 2.5 min), but not inorganic phosphate or uridine, reversibly potentiated the Ca2+ response to PTH (0.1 microM) by 11 +/- 2-fold (mean +/- SEM; n = 39). In contrast, UDP did not affect the cAMP response to PTH, indicating a selective action on Ca2+ signaling. Potentiation of the Ca2+ signal was still observed in the absence of extracellular Ca2+, establishing that nucleotides enhance PTH-induced release of Ca2+ from intracellular stores. Studies using selective purinoceptor agonists suggest that potentiation of PTH signaling is mediated by the P2U receptor subtype. In vivo, nucleotides released during trauma or inflammation may modulate PTH-induced Ca2+ signaling in osteoblasts.
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PMID:Extracellular nucleotides potentiate the cytosolic Ca2+, but not cyclic adenosine 3', 5'-monophosphate response to parathyroid hormone in rat osteoblastic cells. 789 78

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is the most potent of the naturally occurring vitamin D metabolites. In rat thyroid FRTL-5 cells, 1,25-(OH)2D3 attenuated the increase in TSH-stimulated adenylyl cyclase activity obtained by removing TSH from the culture medium. When cells were incubated with 1,25-(OH)2D3 (10 nmol/liter; 4 days), the binding capacity for specific [125I]TSH binding decreased from 20.1 +/- 1.8 to 8.8 +/- 1.6 fmol/10(6) cells (mean +/- SEM; n = 4; P < 0.01) compared to that in control cells. The Kd did not change (mean +/- SEM, 0.46 +/- 0.09 vs. 0.25 +/- 0.07 nmol/liter; n = 4; P = NS). Western blotting revealed no change in the membrane content of the adenylyl cyclase (AC) stimulatory guanine nucleotide-binding protein (G-protein) alpha-subunit (Gs alpha) during 1,25-(OH)2D3 treatment. Similarly, levels of the AC inhibitory G-protein Gi-3 alpha- and G-protein beta-subunits were not altered by 1,25-(OH)2D3. However, Western blotting with antibodies recognizing both Gi-1 alpha and Gi-2 alpha was augmented 4-fold, presumably representing an increase in Gi-2 alpha only, as Gi-1 alpha messenger RNA (mRNA) was not detected in FRTL-5 cells. 1,25-(OH)2D3 (10 nmol/liter; 4 days) reduced cholera toxin (10 nmol/liter)-stimulated AC activity to 85% of the control value (P < 0.05), whereas forskolin (100 mumol/liter)-stimulated direct activation of AC was inhibited by 39%. The TSH receptor mRNA level correlated to the beta-actin mRNA was 2-fold higher in control cells compared to that in 1,25-(OH)2D3-treated cells 12 h after TSH removal. Only minor alterations in the Gs alpha mRNA/beta-actin mRNA and Gi-3 alpha mRNA/beta-actin mRNA ratios were observed during 1,25-(OH)2D3 treatment, whereas Gi-2 alpha mRNA increased 3-fold compared to that in control cells. No change in the resting intracellular Ca2+ concentration could be detected after 4 days of 1,25-(OH)2D3 treatment. Our studies show that 1,25-(OH)2D3 attenuates AC activity by reducing the TSH receptor number and increasing the level of the AC inhibitory G-protein Gi-2 alpha in FRTL-5 cells.
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PMID:1,25-Dihydroxyvitamin D3 attenuates adenylyl cyclase activity in rat thyroid cells: reduction of thyrotropin receptor number and increase in guanine nucleotide-binding protein Gi-2 alpha. 803 8

We previously reported that the adenosine receptor agonist N6-phenylisopropyladenosine (R-PIA) inhibits adenylyl cyclase in detergent-permeabilized embryonic chick ventricular myocytes in the presence of the adrenergic receptor agonist, isoproterenol (Ma and Green 1992). The slope of the dose response curve of this inhibition is very shallow (nH 0.3-0.4). The present studies on detergent-permeabilized chick myocytes evaluate the mechanisms underlying this shallow inhibition curve. We find that in contrast to R-PIA, two additional adenosine receptor agonists, N6-cyclopentyladenosine (CPA) and 2-chloro-N6-cyclopentyladenosine (CCPA), inhibit cardiac adenylyl cyclase activity in a monophasic, dose-dependent manner (nH approximately 1). Two A1 adenosine receptor antagonists, 8-cyclopentyl-1,3,-dipropylxanthine (CPX) and 3-(4-amino)phenethyl-1-propyl-8-cyclopentylxanthine (BW-A884U) affect the R-PIA responses differently. BW-A884U shifts the R-PIA dose response curve to the right in a parallel fashion while CPX both shifts the R-PIA response curve and increases its steepness. Cardiac A1 adenosine receptors were further characterized using one antagonist ([3H]CPX) and two agonist ([3H]R-PIA and [3H]CCPA) radioligands. [3H]CPX binds to the adenosine receptors in detergent-permeabilized ventricular myocytes with a Kd value of 3.3 +/- 0.2 nM and a BMAX value of 30.1 +/- 2.4 fmol/mg protein (means +/- SEM; N = 4). [3H]R-PIA detects more sites than [3H]CCPA (22.8 +/- 4.0 and 8.3 +/- 1.3 fmol/mg protein, respectively; GTP-free conditions). CPA and CCPA inhibit [3H]R-PIA binding in a shallow, dose-dependent manner (nH approximately 0.4), while R-PIA and CPA inhibit [3H]CCPA binding with a nH approximately 1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptor-mediated inhibition of cardiac adenylyl cyclase activity may involve multiple receptor subtypes. 813 4

Human adipocytes are responsive to both alpha- (antilipolytic) and beta-(lipolytic) actions of catecholamine agonists. These effects are mediated by G proteins which interact with adenylcyclase beta 1- and beta 2-adrenoreceptor (AR) subtypes are identified in human adipose tissue. The existence of a third beta-adrenergic (beta 3) receptor has been recently proposed. The beta 3-AR has been reported to mediate catecholamine-induced cAMP accumulation and to be more responsive in this regard than either the beta 1- or the beta 2-AR. To examine the possibility that a beta 3-AR plays a significant role in the control of catecholamine-stimulated lipolysis in human adipose tissue, we used a sensitive in vitro measure of lipolysis. Abdominal and gluteal sc adipose tissue samples from 14 adults were incubated with isoproterenol, a nonspecific beta-AR agonist which activates adenylyl cyclase via all three beta-AR subtypes, in the presence of varying concentrations of a beta-AR antagonist, alprenolol, which blocks the beta 1- and beta 2-AR, but not the beta 3-AR. In tissue from both abdominal and gluteal sites, alprenolol (10(-3) M) completely abolished the lipolytic response to isoproterenol (10(-6) M). Alprenolol (10(-3) M) alone reduced basal lipolysis by 10.2 +/- 2.2% (SEM) in abdominal tissue (P < 0.01), and 7.1 +/- 2.7% in gluteal tissue (P < 0.05). In the presence of alprenolol (10(-3) M), isoproterenol (10(-6) M) had no demonstrable lipolytic effect. The probability of incorrect acceptance of the null hypothesis that isoproterenol had no effect on lipolysis in alprenolol-blocked tissue is P beta < 0.05 for both depots. As an additional control, pooled inguinal adipose tissue from adult male Sprague-Dawley rats was incubated with the same concentrations of alprenolol. Rat adipose tissue has been previously shown to express the beta 3-adrenoreceptor and lipolysis was increased in rat adipose tissue in the presence of alprenolol 10(-4) M and 10(-5) M. We conclude that beta 3-ARs, if present in human adipocyte plasma membranes, do not significantly affect rates of lipolysis.
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PMID:Lack of beta 3-adrenergic effect on lipolysis in human subcutaneous adipose tissue. 839 82


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