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Adenylate Cyclase (adenylate + cyclase)

Distribution by Scientific Domains

Life Sciences	51%
Medical Sciences	36%
Chemistry	12%

Terms modified by Adenylate Cyclase

adenylate cyclase activity

adenylate cyclase inhibitor

Selected Abstracts

Involvement of adenylate cyclase and tyrosine kinase signaling pathways in response of crayfish stretch receptor neuron and satellite glia cell to photodynamic treatment

GLIA, Issue 3 2005
Anatoly Uzdensky
Abstract Neuroglial interactions are most profound during development or damage of nerve tissue. We studied the responses of crayfish stretch receptor neurons (SRN) and satellite glial cells to photosensitization with sulfonated aluminum phthalocyanine Photosens. Although Photosens was localized mainly in the glial envelope, neurons were very sensitive to photodynamic treatment. Photosensitization gradually inhibited and then abolished neuron activity. Neuronal and glial nuclei shrank. Some neurons and glial cells lost the integrity of the plasma membrane and died through necrosis after the treatment. The nuclei of other glial cells but not neurons become fragmented, indicating apoptosis. The number of glial nuclei around neuron soma increased, probably indicating proliferation for enhanced neuron protection. Adenylate cyclase (AC) inhibition by MDL-12330A, or tyrosine kinase (TK) inhibition by genistein, shortened neuron lifetime, whereas AC activation by forskolin or protein tyrosine phosphatases (PTP) inhibition by sodium orthovanadate prolonged neuronal activity. Therefore, cAMP and phosphotyrosines produced by AC and TK, respectively, protected SRN against photoinactivation. AC inhibition reduced photodamage of the plasma membrane and subsequent necrosis in neuronal and glial cells. AC activation prevented apoptosis in photosensitized glial cells and stimulated glial proliferation. TK inhibition protected neurons but not glia against photoinduced membrane permeabilization and subsequent necrosis whereas PTP inhibition more strongly protected glial cells. Therefore, both signaling pathways involving cAMP and phosphotyrosines might contribute to the maintenance of neuronal activity and the integrity of the neuronal and glial plasma membranes. Adenylate cyclase but not phosphotyrosine signaling pathways modulated glial apoptosis and proliferation under photooxidative stress. © 2004 Wiley-Liss, Inc. [source]

Mechanism of association of adenylate cyclase toxin with the surface of Bordetella pertussis: a role for toxin,filamentous haemagglutinin interaction

MOLECULAR MICROBIOLOGY, Issue 6 2002
Franca R. Zaretzky
Summary Adenylate cyclase (AC) toxin from Bordetella per-tussis is unusual in that, unlike most other members of the repeats-in-toxin family that are released into the extracellular milieu, it remains associated with the bacterial surface. In this study, we investigated the nature of the association of this toxin with the surface of B. pertussis. AC toxin was extracted from crude outer membrane preparations of B. pertussis with 8 M urea, but only partially with alkaline sodium carbonate and not at all with octylglucoside, suggesting that denaturation of the toxin is necessary for its removal from the membrane. B. pertussis mutants lacking filamentous haemagglutinin (FHA) released significantly more AC toxin into the medium, and AC toxin association with the bacterial surface was partially restored by expression of FHA from a plasmid, suggesting a role for FHA in surface retention of AC toxin. AC toxin distribution was unaffected by the absence of pertactin, or full-length lipopolysaccharide, or a defect in secretion of pertussis toxin. Using overlay and immunoprecipitation, we found that a direct physical association can occur between AC toxin and FHA. Combined, these findings suggest that FHA may play a role in AC toxin retention on the surface of B. pertussis and raise the possibility of an involvement of adherence mediated by FHA in delivery of AC toxin from the bacterium to the target cell. [source]

Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses

DEVELOPMENTAL NEUROBIOLOGY, Issue 3 2006
Linda A. Santschi
Abstract Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2,R,3,R)-2-(2,,3,-dicarboxy-cyclopropyl) glycine (DCGIV; 5 ,M), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 ,M), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 ,M) was combined with a cell-permeant PKA inhibitor H-89 (10 ,M), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 ,M), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 ,M), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6 -cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 ,M), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]

Discovery and recognition of purine receptor subtypes on platelets

DRUG DEVELOPMENT RESEARCH, Issue 1-2 2001
Susanna M.O. HouraniArticle first published online: 9 MAY 200
Abstract The effects of purines on platelets have been known since the 1960s, when Born demonstrated aggregation induced by ADP and its inhibition by adenosine and by ATP. The inhibition by adenosine is not specific for ADP, and adenosine acts at a separate receptor to stimulate adenylate cyclase, which has an inhibitory effect on platelet function. Studies using selective agonists and antagonists have shown that the platelet receptor is of the A2A subtype and this has been confirmed using A2A knockout mice. The situation with ADP is more complex, and there has been controversy about the number of ADP receptors on platelets. ADP causes shape change, aggregation, mobilisation of calcium from intracellular stores, rapid calcium influx, and inhibition of adenylate cyclase, and the relationship between these is becoming clearer. Two cloned P2 receptors have been detected on platelets, P2X1 and P2Y1, and a third P2Y receptor is thought to exist. The P2X1 receptor is responsible for the rapid calcium influx and can be activated by ATP as well as by ADP, but is likely to be desensitised under normal experimental conditions and its pathophysiological role is uncertain. The P2Y1 receptor is responsible for calcium mobilisation, shape change, and the initiation of aggregation, and these responses are abolished in P2Y1 knockout mice, while the other P2Y receptor is responsible for inhibition of adenylate cyclase and is required for full aggregation. ATP is a competitive antagonist at both these P2Y receptors, while some nucleotide analogues can discriminate between them. Drug Dev. Res. 52:140,149, 2001. © 2001 Wiley-Liss, Inc. [source]

Atrazine increases the sodium absorption in frog (Rana esculenta) skin

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2006
Giuseppe Cassano
Abstract The presence of atrazine in agricultural sites has been linked to the decline in amphibian populations. The efforts of the scientific community generally are directed toward investigating the long-term effect of atrazine on complex functions (reproduction or respiration), but in the present study, we investigated the short-term effect on the short-circuit current (ISC), a quantitative measure of the ion transport operated by frog (Rana esculenta) skin. Treatment with 5 ,M atrazine (1.08 mg/L) does not affect the transepithelial outfluxes of [14C]mannitol or [14C]urea; therefore, atrazine does not damage the barrier properties of frog skin. Atrazine causes a dose-dependent increase in the short-circuit current, with a minimum of 4.64 ± 0.76 ,A/cm2 (11.05% ± 1.22%) and a maximum of 12.7 ± 0.7 ,A/cm2 (35% ± 2.4%) measured at 10 nM and 5 ,M, respectively. An increase in ISC also is caused by 5 ,M ametryne, prometryn, simazine, terbuthylazine, or terbutryn (other atrazine derivatives). In particular, atrazine increases the transepithelial 22Na+ influx without affecting the outflux. Finally, stimulation of ISC by atrazine is suppressed by SQ 22536, H89, U73122, 2-aminoethoxydiphenyl borate, and W7 (blockers of adenylate cyclase, protein kinase A, phospholipase C, intracellular Ca2+ increase, and calmodulin, respectively), whereas indomethacin and calphostin C (inhibitors of cyclooxygenase and protein kinase C, respectively) have no effect. [source]

Potentiation of glycine responses by dideoxyforskolin and tamoxifen in rat spinal neurons

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2003
Dominique Chesnoy-Marchais
Abstract Dideoxyforskolin, a forskolin analogue unable to stimulate adenylate cyclase, and tamoxifen, an antioestrogen widely used against breast cancer, are both known to block some Cl, channels. Their effects on Cl, responses to glycine or GABA have been tested here by using whole-cell recording from cultured spinal neurons. Dideoxyforskolin (4 or 16 µm) and tamoxifen (0.2,5 µm) both potentiate responses to low glycine concentrations. They also induce blocking effects, predominant at high glycine concentrations. At 5 µm, tamoxifen increased responses to 15 µm glycine by a factor >4.5, reaching 20 in some neurons. Potentiation by extracellular dideoxyforskolin or tamoxifen persisted after intracellular application of the modulator and was not due to Zn2+ contamination. Potentiation by tamoxifen also persisted in a Ca2+ -free extracellular solution, after intracellular Ca2+ buffering and protein kinase C blockade. Thus, the critical sites of action are not intracellular. The EC50 for glycine was lowered 6.6-fold by 5 µm tamoxifen. The kinetics and voltage-dependence of the effects of tamoxifen on glycine responses support the idea that this hydrophobic drug may act from a site located within the membrane. Tamoxifen (5 µm) also increased responses to 2 µm GABA by a factor of 3.5, but barely affected peak responses to 20 µm GABA. The demonstration that tamoxifen affects some of the main inhibitory receptors should be useful for better evaluating its neurological effects. Furthermore, the results identify a new class of molecules that potentiate glycine receptor function. [source]

Differential galanin receptor-1 and galanin expression by 5-HT neurons in dorsal raphé nucleus of rat and mouse: evidence for species-dependent modulation of serotonin transmission

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003
Jari A. Larm
Abstract Galanin and galanin receptors are widely expressed by neurons in rat brain that either synthesize/release and/or are responsive to, classical transmitters such as ,-aminobutyric acid, acetylcholine, noradrenaline, histamine, dopamine and serotonin (5-hydroxytryptamine, 5-HT). The dorsal raphé nucleus (DRN) contains , 50% of the 5-HT neurons in the rat brain and a high percentage of these cells coexpress galanin and are responsive to exogenous galanin in vitro. However, the precise identity of the galanin receptor(s) present on these 5-HT neurons has not been previously established. Thus, the current study used a polyclonal antibody for the galanin receptor-1 (GalR1) to examine the possible expression of this receptor within the DRN of the rat and for comparative purposes also in the mouse. In the rat, intense GalR1-immunoreactivity (IR) was detected in a substantial population of 5-HT-immunoreactive neurons in the DRN, with prominent receptor immunostaining associated with soma and proximal dendrites. GalR1-IR was also observed in many cells within the adjacent median raphé nucleus. In mouse DRN, neurons exhibited similar levels and distribution of 5-HT-IR to that in the rat, but GalR1-IR was undetectable. Consistent with this, galanin and GalR1 mRNA were also undetectable in mouse DRN by in situ hybridization histochemistry, despite the detection of GalR1 mRNA (and GalR1-IR) in adjacent cells in the periaqueductal grey and other midbrain areas. 5-HT neuron activity in the DRN is primarily regulated via 5-HT1A autoreceptors, via inhibition of adenylate cyclase and activation of inward-rectifying K+ channels. Notably, the GalR1 receptor subtype signals via identical mechanisms and our findings establish that galanin modulates 5-HT neuron activity in the DRN of the rat via GalR1 (auto)receptors. However, these studies also identify important species differences in the relationship between midbrain galanin and 5-HT systems, which should prompt further investigations in relation to comparative human neurochemistry and which have implications for studies of animal models of relevant neurological conditions such as stress, anxiety and depression. [source]

Phosphorylation of voltage-gated ion channels in rat olfactory receptor neurons

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2001
Christian H. Wetzel
Abstract In olfactory receptor neurons (ORNs), ligand,odorant receptor interactions cause G protein-mediated activation of adenylate cyclase and a subsequent increase in concentration of the intracellular messenger cAMP. Odorant-evoked elevation in cAMP is thought to directly activate a cation-selective cyclic nucleotide-gated channel, which causes external Ca2+ influx, leading to membrane depolarization and the generation of action potentials. Our data show that in freshly dissociated rat ORNs, odorant-induced elevation in cAMP also activates cAMP-dependent protein kinase (PKA), which is then able to phosphorylate various protein targets in the olfactory signal transduction pathway, specifically voltage-gated sodium and calcium channels. The presence of PKI (PKA inhibitor peptide) blocked the modulatory action of cAMP on voltage-gated ion channels. By modulating the input/output properties of the sensory neurons, this mechanism could take part in the complex adaptation process in odorant perception. In addition, we found modulation of voltage-gated sodium and calcium channel currents by 5-hydroxytryptamine and the dopamine D1 receptor agonist SKF 38393. These findings suggest that in situ ORNs might also be a target for efferent modulation. [source]

Molecular and functional characterization of novel CRFR1 isoforms from the skin

FEBS JOURNAL, Issue 13 2004
Alexander Pisarchik
In our continued studies on corticotropin releasing factor receptor (CRFR1) signaling in the skin, we tested functional activity of CRFR1,, e, f, g and h isoforms after transfection to COS cells. Both membrane-bound and soluble variants are translated in vivo into final protein products that undergo further post-translational modifications. CRFR1, was the only isoform coupled directly to adenylate cyclase with the exception of an artificial isoform (CRFR1h2) with the insertion of 37 amino acids between the ligand binding domain and the first extracellular loop that was capable of producing detectable levels of cyclic AMP (cAMP). Soluble isoforms could modulate cell response with CRFR1e attenuating and CRFR1h amplifying CRFR1,-coupled cAMP production stimulated by urocortin. Testing with plasmids containing the luciferase reporter gene, and inducible cis -elements (CRE, CaRE, SRE, AP1 or NF-,B) demonstrated that only CRFR1, was involved directly in the transcriptional regulation, while CRFR1g inhibited CRE activity. Significantly higher reporter gene expression by CRF was observed than that mediated by 4,-phorbol 12-myristate 13-acetate and forskolin alone, being compatible with the concomitant treatment by phorbol 12-myristate 13-acetate and forskolin. This suggests that both protein kinase A and C can be involved in CRF-dependent signal transduction. [source]

Cross-talk between olfactory second messenger pathways

FEBS JOURNAL, Issue 14 2000
Alexander Vogl
The second messengers 3,-5,-cyclic-monophosphate (cAMP) and inositol 1,4,5-trisphosphate (InsP3) have been implicated in olfactory signal transduction in various species. The results of the present study provide evidence that the two olfactory second messenger pathways in rat olfactory neurons do not work independently but rather show a functional antagonism: whereas inhibition of phospholipase C (PLC) in isolated olfactory cilia by U-73122 led to an augmentation of odor-induced cAMP signaling, activation of the phosphoinositol pathway resulted in attenuation of odor-induced cAMP formation. Furthermore, this study indicates that elevated cAMP levels cause suppression of odor-induced InsP3 signaling, whereas inhibition of adenylate cyclase (AC) by cisN -(2-phenylcyclopentyl)azacylotridec-1-en-2-amine (MDL-12,330 A) results in potentiation of odor-induced InsP3 formation. Concerning the molecular mechanism involved in cross-interaction, the experimental data indicate that the observed antagonism of elevated cAMP is based on inhibition of PLC activation rather than on stimulation of InsP3 degradation. As blockage of the endogenous protein kinase A (PKA) prevented the inhibitory effect of cAMP, the suppression of odor-induced InsP3 signaling by cAMP may be mediated by a PKA-controlled reaction. [source]

The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets

FEBS JOURNAL, Issue 8 2000
Carol Dangelmaier
U46619, a thromboxane A2 mimetic, but not ADP, caused activation of p38 mitogen activated protein (MAP) kinase in aspirin-treated platelets. In nonaspirinated human platelets ADP activated p38 MAP kinase in both a time-and concentration-dependent manner, suggesting that ADP-induced p38 MAP kinase activation requires generation of thromboxane A2. However, neither a thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 and a thromboxane synthase inhibitor, furegrelate, either alone or together, nor indomethacin blocked ADP-induced p38 kinase activation in nonaspirinated platelets. Other cycloxygenase products, PGE2, PGD2, and PGF2,, failed to activate p38 kinase in aspirin-treated platelets. Hence, ADP must be generating an agonist, other than thromboxane A2, via an aspirin-sensitive pathway, which is capable of activating p38 kinase. AR-C66096, a P2TAC (platelet ADP receptor coupled to inhibition of adenylate cyclase) antagonist, did not inhibit ADP-induced p38 MAP kinase activation. The P2X receptor selective agonist, ,,,-methylene ATP, failed to activate p38 MAP kinase. On the other hand, the P2Y1 receptor selective antagonist, adenosine-2,-phosphate-5,-phosphate inhibited ADP-induced p38 kinase activation in a concentration-dependent manner, indicating that the P2Y1 receptor alone mediates ADP-induced generation of the p38 kinase-activating factor. These results demonstrate that ADP causes the generation of a factor in human platelets, which can activate p38 kinase, and that this response is mediated by the P2Y1 receptor. Neither the P2TAC receptor nor the P2X1 receptor has any significant role in this response. [source]

Involvement of adenylate cyclase and tyrosine kinase signaling pathways in response of crayfish stretch receptor neuron and satellite glia cell to photodynamic treatment

An abnormal gene expression of the ,-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats,

HEPATOLOGY, Issue 6 2008
Giulio Ceolotto
Decreased cardiac contractility and ,-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study ,-adrenergic,stimulated contractility and ,-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10,10 to 10,6 M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha,inhibiting subunit 2 (G,i2), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of G,i2, PDE2a, and RGS2 down-regulates the ,-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy. (HEPATOLOGY 2008;48:1913-1923.) [source]

B96Bom encodes a Bombyx mori tyramine receptor negatively coupled to adenylate cyclase

INSECT MOLECULAR BIOLOGY, Issue 3 2003
H. Ohta
Abstract A cDNA encoding a biogenic amine receptor (B96Bom) was isolated from silkworm (Bombyx mori) larvae, and the ligand response of the receptor stably expressed in HEK-293 cells was examined. Tyramine (TA) at 0.1,100 µm reduced forskolin (10 µm)-stimulated intracellular cAMP levels by approximately 40%. The inhibitory effect of TA at 1 µm was abolished by yohimbine and chlorpromazine (each 10 µm). Although octopamine (OA) also reduced the cAMP levels, the potency was at least two orders of magnitude lower than that of TA. Furthermore, unlabelled TA (IC50 = 5.2 nm) inhibited specific [3H]TA binding to the membranes of B96Bom-transfected HEK-293 cells more potently than did OA (IC50 = 1.4 µm) and dopamine (IC50 = 1.7 µm). Taken together with the result of phylogenetic analysis, these findings indicate that the B96Bom receptor is a B. mori TA receptor, which is negatively coupled to adenylate cyclase. The use of this expression system should facilitate physiological studies of TA receptors as well as structure,activity studies of TA receptor ligands. [source]

Expression of glutathione transferase isoenzymes in the human H295R adrenal cell line and the effect of forskolin

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2002
Tuula Stark
Abstract In previous studies in our laboratory (L. Mankowitz, L. Staffas, M. Bakke, and J. Lund, Biochem J, 1995, 305, 111,118; L. Staffas, L. Mankowitz, M. Söderström, A. Blanck, I. Porsch-Hällström, C. Sundberg, B. Mannervik, B. Olin, J. Rydström, and J.W. DePierre, Biochem J, 1992, 286, 65,72) isoenzymes of GST, primarily of the , class, have been shown to be downregulated by adrenocorticotropic hormone (ACTH) in rat and mouse adrenal cells. In the present investigation the human adrenal H295R cell line (W.E. Rainey, I.M. Bird, and J.I. Mason, Mol Cell Endocrinol, 1994, 100, 45,50) was examined in a similar manner. Analysis by reverse-phase HPLC revealed that these cells express four isoenzymes of GST, i.e., A1, A2, P1, and M4, as well as another unidentified protein that was retained by our affinity column (elution time of 32 min) and, thus, presumably binds glutathione. Among these forms, A1 was present at the highest level. Upon addition of forskolin (an activator of adenylate cyclase which has been shown previously to mimic the effect of ACTH on adrenal cells) to the culture medium, the level of A1 decreased approximately 70% by forskolin, whereas the levels of the other isoenzymes were slightly increased, and that of the unknown form doubled. Thus, the influence of ACTH on expression of GST isoenzymes in this human adrenal cell line differs from that in rat and mouse adrenal cells. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:169,173, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10034 [source]

Agonist-induced internalization of histamine H2 receptor and activation of extracellular signal-regulated kinases are dynamin-dependent

JOURNAL OF NEUROCHEMISTRY, Issue 1 2008
A-Jing Xu
Abstract Histamine H2 receptor (H2R) is a member of G protein-coupled receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the receptor, activation of extracellular signal-regulated kinases ERK1/2, and receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself. [source]

A family of octapamine receptors that specifically induce cyclic AMP production or Ca2+ release in Drosophila melanogaster

JOURNAL OF NEUROCHEMISTRY, Issue 2 2005
Sabine Balfanz
Abstract In invertebrates, the biogenic-amine octopamine is an important physiological regulator. It controls and modulates neuronal development, circadian rhythm, locomotion, ,fight or flight' responses, as well as learning and memory. Octopamine mediates its effects by activation of different GTP-binding protein (G protein)-coupled receptor types, which induce either cAMP production or Ca2+ release. Here we describe the functional characterization of two genes from Drosophila melanogaster that encode three octopamine receptors. The first gene (Dmoa1) codes for two polypeptides that are generated by alternative splicing. When heterologously expressed, both receptors cause oscillatory increases of the intracellular Ca2+ concentration in response to applying nanomolar concentrations of octopamine. The second gene (Dmoa2) codes for a receptor that specifically activates adenylate cyclase and causes a rise of intracellular cAMP with an EC50 of ,3 × 10,8 m octopamine. Tyramine, the precursor of octopamine biosynthesis, activates all three receptors at ,,100-fold higher concentrations, whereas dopamine and serotonin are non-effective. Developmental expression of Dmoa genes was assessed by RT,PCR. Overlapping but not identical expression patterns were observed for the individual transcripts. The genes characterized in this report encode unique receptors that display signature properties of native octopamine receptors. [source]

Heterodimerization of opioid receptor-like 1 and µ-opioid receptors impairs the potency of µ receptor agonist

JOURNAL OF NEUROCHEMISTRY, Issue 6 2005
Hung-Li Wang
Abstract Nociceptin activation of ORL1 (opioid receptor-like 1 receptor) has been shown to antagonize µ receptor-mediated analgesia at the supraspinal level. ORL1 and µ-opioid receptor (µR) are co-expressed in several subpopulations of CNS neurons involved in regulating pain transmission. The amino acid sequence of ORL1 also shares a high degree of homology with that of µ receptor. Thus, it is hypothesized that ORL1 and µR interact to form the heterodimer and that ORL1/µR heterodimerization may be one molecular basis for ORL1-mediated antiopioid effects in the brain. To test this hypothesis, myc-tagged ORL1 and HA-tagged µR are co-expressed in human embryonic kidney (HEK) 293 cells. Co-immunoprecipitation experiments demonstrate that ORL1 dimerizes with µR and that intracellular C-terminal tails of ORL1 and µR are required for the formation of ORL1/µR heterodimer. Second messenger assays further indicate that formation of ORL1/µR heterodimer selectively induces cross-desensitization of µR and impairs the potency by which [d -Ala2,N -methyl-Phe4,Gly-ol5]enkephalin (DAMGO) inhibits adenylate cyclase and stimulates p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation. These results provide the evidence that ORL1/µR heterodimerization and the resulting impairment of µ receptor-activated signaling pathways may contribute to ORL1-mediated antiopioid effects in the brain. [source]

Differential In Vitro Secretion of Gonadotropin-Releasing Hormone (GnRH) and [Hydroxyproline9]GnRH from the Rat Hypothalamus During Postnatal Development

JOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2000
L. Rochdi
Abstract The differential secretion of gonadotropin-releasing hormone (GnRH) and [hydroxyproline9]GnRH (HypGnRH) has been recently reported from the adult rat hypothalamus. We report here in vitro cosecretion of HypGnRH and GnRH by the hypothalamus of 2,45 day-old-rats and provide evidence that they are differentially regulated throughout development. The secretion of both forms of GnRH was increased in a dependent manner during depolarization by high K+ solutions, and was stimulated by forskolin and 12- O -tetradecanoylphorbol-13-acetate (TPA), activators of adenylate cyclase and protein kinase C pathways, respectively. The proportion of HypGnRH in the release of GnRH-like peptides remained stable and high (33,40%) under basal and K+ -induced conditions until days 13 and 21, respectively. By contrast, the proportion of HypGnRH in the total GnRH-like content of the developing hypothalamus continuously decreased (from 37% to 14%). Similarly, the proportion of HypGnRH: total GnRH-like material released remained stable in TPA- (30%) and forskolin- (50%) induced secretion until postnatal day 8. Evaluation of release over tissue store ratios revealed a 1.3-to 2.8-fold higher release of HypGnRH compared to GnRH according to the different secretions and postnatal periods examined. The preferential recruitment of HypGnRH was maintained under basal and K+ conditions during postnatal development, but it disappeared under TPA stimulation from day 13 onwards. After forskolin stimulation, the preferential mobilization of HypGnRH was markedly reduced from day 2 to day 13 but recovered its high perinatal level during puberty. Taken together, our results support the hypothesis that HypGnRH may play a specific role in development. In addition, a specific function of this peptide taking place during puberty through the activation of the adenylate cyclase pathway is suggested. [source]

Beer-Induced Pancreatic Enzyme Secretion: Characterization of Some Signaling Pathways and of the Responsible Nonalcoholic Compounds

ALCOHOLISM, Issue 9 2009
Andreas Gerloff
Background:, Various alcoholic beverages have different effects on pancreatic enzyme secretion in vivo and in vitro. Recently we demonstrated that beer dose-dependently induces amylase release of rat pancreatic acinar cells, whereas pure ethanol and other alcoholic beverages have no effect. The aims of this study were to: (1) investigate the involved signaling pathways in the beer-induced enzyme secretion of rat pancreatic acinar cells and (2) characterize the responsible nonalcoholic compounds from beer. Methods:, Rat pancreatic AR4-2J cells were differentiated by dexamethasone treatment for 72 hours. After incubation of cells with 1 to 10% (v/v) beer (containing 4.7% v/v ethanol) in the absence or presence of the maximal effective concentration of cholecystokinin (CCK) (100 nM) for 60 minutes, protein secretion was measured using amylase activity assay. To study the involved signaling pathways, cells were pretreated with selective inhibitors or the fluorescent dye Fura2/AM for 15 and 30 minutes, respectively. To characterize the responsible compounds, beer was distilled, lyophilized, dialyzed, or treated with proteases prior stimulation of the cells. Extract of barley was prepared by boiling the crop and subsequent filtration. Results:, Stimulation with 5% and 10% beer (v/v) significantly (p < 0.001) increased maximally CCK-induced amylase by 55 ± 25% and 56 ± 37%, respectively. By using selective antagonists, we found that inhibition of phospholipase C (PLC) and inositol 1,4,5-trisphosphate-receptor binding reduced beer-induced amylase release, whereas inhibition of protein kinase C, adenylate cyclase, and protein kinase A had no significant effect. Using the fluorescent Ca2+ indicator Fura-2/AM revealed that beer induces an increase of cytosolic free Ca2+ concentration. Stimulation of AR4-2J cells with preproducts of beer and fermented glucose indicated that the stimulatory substances from beer derived from barley and are not produced during alcoholic fermentation. Furthermore, the stimulants from beer are thermostable, nonvolatile substances with a molecular weight higher than 15 kDa. Conclusions:, Beer-induced enzyme secretion of AR4-2J cells is, at least in part, mediated by the activation of PLC and subsequent Ca2+ release from internal stores. However, the additive effect of beer on CCK-induced amylase release suggests that additional signaling pathways are involved. The yet unknown stimulants of pancreatic enzyme secretion originate from barley and their stimulatory potential is maintained during the process of malting and brewing. [source]

Cloning and pharmacological characterization of the equine adenosine A2A receptor: a potential therapeutic target for the treatment of equine endotoxemia

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2006
C. I. BRANDON
The aim of the current study was to clone the equine adenosine A2A receptor gene and to establish a heterologous expression system to ascertain its pharmacologic profile via radioligand binding and functional assays. An eA2A -R expression construct was generated by ligation of the eA2A cDNA into the pcDNA3.1 expression vector, and stably transfected into human embryonic kidney cells (HEK). Binding assays identified those clones expressing the eA2A -R, and equilibrium saturation isotherm experiments were utilized to determine dissociation constants (KD), and receptor densities (Bmax) of selected clones. Equilibrium competition binding revealed a rank order of agonist potency of ATL > CV-1808 > NECA > 2-CADO > CGS21680, and a rank order of antagonist potency as ZM241385 > 8-phenyltheophylline > p -sulfophenyltheophylline > caffeine. Furthermore, adenylate cyclase assays using selective A2A -R agonists revealed that the eA2A -R functionally coupled to G,s as indicated by an increase in intracellular [3H]cAMP upon receptor activation. Finally, NF- ,B reporter gene assays revealed a CGS21680 concentration-dependent inhibition of NF- ,B activity. These results indicate that the heterologously expressed eA2A -R has a pharmacological profile similar to that of other mammalian A2A receptors and thus can be utilized for further characterization of the eA2A -R to ascertain whether it can serve as a suitable pharmacological target for equine inflammatory disease. [source]

Cannabinoid signalling in the enteric nervous system

NEUROGASTROENTEROLOGY & MOTILITY, Issue 9 2009
J. J. Galligan
Abstract, Cannabinoid signalling is an important mechanism of synaptic modulation in the nervous system. Endogenous cannabinoids (anandamide and 2-arachidonyl-glycerol) are synthesized and released via calcium-activated biosynthetic pathways. Exogenous cannabinoids and endocannabinoids act on CB1 and CB2 receptors. CB1 receptors are neuronal receptors which couple via G-proteins to inhibition of adenylate cyclase or to activation or inhibition of ion channels. CB2 receptors are expressed by immune cells and cannabinoids can suppress immune function. In the central nervous system, the endocannabinoids may function as retrograde signals released by the postsynaptic neuron to inhibit neurotransmitter release from presynaptic nerve terminals. Enteric neurons also express CB receptors. Exogenously applied CB receptor agonists inhibit enteric neuronal activity but it is not clear if endocannabinoids released by enteric neurons can produce similar responses in the enteric nervous system (ENS). In this issue of Neurogastroenterology and Motility, Boesmans et al. show that CB1 receptor activation on myenteric neurons maintained in primary culture can suppress neuronal activity, inhibit synaptic transmission and mitochondrial transport along axons. They also provide initial evidence that myenteric neurons (or other cell types present in the cultures) release endocannabinoids and which activate CB1 receptors constitutively. These data provide new information about targets for cannabinoid signalling in the ENS and highlight the potential importance of CB receptors as drug targets. It is necessary that future work extends these interesting findings to intact tissues and ideally to the in vivo setting. [source]

A Phytochrome-like Protein AphC Triggers the cAMP Signaling Induced by Far-red Light in the Cyanobacterium Anabaena sp.

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2004
Strain PCC7120
ABSTRACT In the filamentous, nitrogen-fixing cyanobacterium Anabaena sp. PCC7120, red light (630 nm) decreased, whereas far-red light (720 nm) increased cellular adenosine 3,,5,-cyclic monophosphate (cAMP) content. To find a red and far-red light photoreceptor that triggers the cAMP signal cascade, we disrupted 10 open reading frame having putative chromophore-binding GAF domains. The response of the cellluar cAMP concentration to red and far-red light in each open reading frame disruptant was determined. It was found that only the mutant of the gene all2699 failed to respond to far-red light. The open reading frame named as aphC encoded a protein with 920 amino acids including GAF domains similar to those involved in Cph2, a photoreceptor of Synechocystis sp. PCC6803. To determine which adenylate cyclase (AC) is responsible for far-red light signal, we disrupted all AC genes and found that CyaC was the candidate. The enzymatic activity of CyaC might be controlled by a far-red light photoreceptor through the phosphotransfer reaction. The site-specific mutant of the Asp59 residue of the receiver (R1) domain of CyaC lost its light-response capability. It was suggested that the far-red light signal was received by AphC and then transferred to the N-terminal response regulator domain of CyaC. Then its catalytic activity was stimulated, which increased the cellular cAMP concentration and drove the subsequent signal transduction cascade. [source]

Single-step affinity purification of recombinant proteins using a self-excising module from Neisseria meningitidis FrpC

PROTEIN SCIENCE, Issue 10 2008
Lenka Sadilkova
Abstract Purification of recombinant proteins is often a challenging process involving several chromatographic steps that must be optimized for each target protein. Here, we developed a self-excising module allowing single-step affinity chromatography purification of untagged recombinant proteins. It consists of a 250-residue-long self-processing module of the Neisseria meningitidis FrpC protein with a C-terminal affinity tag. The N terminus of the module is fused to the C terminus of a target protein of interest. Upon binding of the fusion protein to an affinity matrix from cell lysate and washing out contaminating proteins, site-specific cleavage of the Asp,Pro bond linking the target protein to the self-excising module is induced by calcium ions. This results in the release of the target protein with only a single aspartic acid residue added at the C terminus, while the self-excising affinity module remains trapped on the affinity matrix. The system was successfully tested with several target proteins, including glutathione-S-transferase, maltose-binding protein, ,-galactosidase, chloramphenicol acetyltransferase, and adenylate cyclase, and two different affinity tags, chitin-binding domain or poly-His. Moreover, it was demonstrated that it can be applied as an alternative to two currently existing systems, based on the self-splicing intein of Saccharomyces cerevisiae and sortase A of Staphylococcus aureus. [source]

Laminin acts via focal adhesion kinase/phosphatidylinositol-3, kinase/protein kinase B to down-regulate ,1 -adrenergic receptor signalling in cat atrial myocytes

THE JOURNAL OF PHYSIOLOGY, Issue 3 2009
Y. G. Wang
We previously reported that short-term (2 h) plating of cat atrial myocytes on the extracellular matrix protein, laminin (LMN) decreases adenylate cyclase activity and ,1 -adrenergic receptor (,1 -AR) stimulation of L-type Ca2+ current (ICa,L). The present study sought to determine whether LMN-mediated down-regulation of ,1 signalling is due to down-regulation of adenylate cyclase and to gain insight into the signalling mechanisms responsible. ,1 -AR stimulation was achieved by 0.01 ,m isoproterenol (isoprenaline) plus 0.1 ,m ICI 118551, a selective ,2 -AR antagonist. Atrial myocytes were plated for at least 2 h on uncoated cover-slips (,LMN) or cover-slips coated with LMN (+LMN). As previously reported, ,1 -AR stimulation of ICa,L was significantly smaller in +LMN compared to ,LMN atrial myocytes. In ,LMN myocytes, 10 ,m LY294002 (LY), a specific inhibitor of PI-(3)K, had no effect on ,1 -AR stimulation of ICa,L. In +LMN myocytes, however, LY significantly increased ,1 -AR stimulation of ICa,L. Western blots revealed that compared with ,LMN myocytes, +LMN myocytes showed a significant increase in Akt phosphorylation at Ser-473, which was prevented by LY. In another approach, +LMN myocytes were infected (multiplicity of infection (MOI), 100; 24 h) with replication-defective adenoviruses (Adv) expressing dominant-negative inhibitors of focal adhesion kinase (FAK) (Adv-FRNK or Adv-Y397F-FAK) or Akt (Adv-dnAkt). Compared with control cells infected with Adv-,-galactosidase, cells infected with Adv-FRNK, Adv-Y397F-FAK or Adv-dnAkt each exhibited a significantly greater ,1 -AR stimulation of ICa,L. In ,LMN myocytes LY had no effect on forskolin (FSK)-stimulated ICa,L. However, in +LMN myocytes LY significantly increased FSK-stimulated ICa,L. Similar results were obtained in +LMN atrial myocytes infected with Adv-FRNK. We conclude that LMN binding to ,1 -integrin receptors acts via FAK/PI-(3)K/Akt to inhibit adenylate cyclase activity and thereby down-regulates ,1 -AR-mediated stimulation of ICa,L. These findings provide new insight into the cellular mechanisms by which the extracellular matrix can modulate atrial ,-AR signalling. [source]

NO/cyclic GMP pathway mediates the relaxation of feline lower oesophageal sphincter

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2003
C. H. Jun
Summary 1 We examined the role of the NO/cyclic GMP (cyclic GMP) pathway in nitric oxide (NO)- and vasoactive intestinal peptide (VIP)-induced relaxation of feline lower oesophageal sphincter (LES). Furthermore, it was studied whether methylene blue, LY83583 and ODQ, which are soluble guanylate cyclase (sGC) inhibitors, could inhibit NO-induced relaxation. 2 The nitric oxide synthase (NOS) inhibitor, N -nitro- l -arginine (l -NNA) had no effect in sodium nitropruside (SNP)-induced relaxation, but 3-morpholinosydnonimine- N -ethylcarbamide (SIN-1)-induced relaxation was decreased by the pretreatment of l -NNA, which showed that SIN-1, not SNP, could activate NOS to cause relaxation. Methylene blue and LY83583 did not inhibit the relaxation by SNP and SIN-1. However, the more specific sGC inhibitor ODQ blocked the relaxation induced by NO donors. 3 To identify the relationship of NOS, sGC and adenylate cyclase in VIP-induced relaxation, tissue were pretreated with l -NNA and ODQ and SQ22536. These inhibitors produced significant inhibition of this response to VIP. The adenylyl cyclase inhibitor SQ 22536 also inhibited relaxation by VIP. 4 In conclusion, our data showed that SNP- and SIN-1-induced relaxation was mediated by sGC. Of sGC inhibitors, methylene blue and LY83583 were not adequate for the examination of NO donor-induced feline LES smooth muscle relaxation. VIP also caused relaxation by the pathway involving NO and cGMP and cAMP. [source]

Teriparatide (Biosynthetic Human Parathyroid Hormone 1,34): A New Paradigm in the Treatment of Osteoporosis

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2004
Kim T. Brixen
Biosynthetic human parathyroid hormone 1,34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2,3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 ,g/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged. [source]

Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D2 -like receptors

BIPOLAR DISORDERS, Issue 3 2007
Liliana P Montezinho
Objective:, The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D2 -like receptors in vitro in rat cortical neurons in culture and in vivo in the rat prefrontal cortex. Methods:, The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the [8- 3H] and [125I] radioimmunoassay kits. Results:,In vitro and in vivo data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels in vitro, but had differential effects in vivo. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both in vitro and in vivo, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D2 -like receptors with quinpirole partially inhibited forskolin-induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex in vivo. However, surprisingly, in carbamazepine-treated rats the activation of dopamine D2 -like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme. Conclusions:, It was shown that each of these drugs affects basal- and forskolin-evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D2 -like receptors activation. [source]

Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in rats

BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2010
R Vidal
BACKGROUND AND PURPOSE The 5-HT4 receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT4 receptor-mediated signalling events. EXPERIMENTAL APPROACH The effects of 21 days treatment (p.o.) with high (40 mg·kg,1) and low (10 mg·kg,1) doses of venlafaxine, were evaluated at different levels of 5-HT4 receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg,1, 21 days) was also evaluated on 5-HT4 receptor density. KEY RESULTS Treatment with a high dose (40 mg·kg,1) of venlafaxine did not alter 5-HT4 mRNA expression, but decreased the density of 5-HT4 receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg,1) while it was attenuated in rats treated with 40 mg·kg,1 of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT4 receptor density. CONCLUSIONS AND IMPLICATIONS Our data indicate a functional desensitization of 5-HT4 receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake. [source]

GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity

BRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2008
H A Overton
GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (,-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G,s coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic ,-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed. British Journal of Pharmacology (2008) 153, S76,S81; doi:10.1038/sj.bjp.0707529; published online 26 November 2007 [source]