• The Korean Journal of Physiology and Pharmacology
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• 제1권3호
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• pp.225-231
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• 1997

As it has been reported that the depolarization-induced norepinephrine (NE) release is modulated by activation of presynaptic $A_1-adenosine$ heteroreceptor and various lines of evidence indicate the involvement of adenylate cyclase system in $A_1-adenosine$ post-receptor mechanism in hippocampus, it was attempted to delineate the role of adenylate cyclase system in the $A_1-receptor-mediated$ control of NE release in this study. Slices from rat hippocampus were equilibrated with $[^3H]-NE$ and the release of the labelled products was evoked by electrical stimulation.(3 Hz, $5Vcm^{-1}$, 2 ms, rectangular pulses). The influence of various agents on the evoked tritium-outflow was investigated. $N^6-Cyclopentyladenosine$ (CPA), a specific $A_1-adenosine$ receptor agonist, in concentrations Tanging from 0.1 to $10{\mu}M$ decreased the $[^3H]-NE$ release in a dose-dependent mauler without any change of basal rate of release. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, $2{\mu}M$), a selective $A_1-receptor$ antagonist, inhibited the CPA effect. The responses to N-ethylmaleimide $(3&10{\mu}M)$, a SH-alkylating agent of G-protein, were characterized by increments of the evoked NE-release and the CPA effects were completely abolished by NEM pretreatment. Forskolin, a specific adenylate cyclase activator, in concentrations ranging from 0.1 to $30{\mu}M$ increased the evoked and basal rate of NE release in a dose-dependent manner and the CPA effects were inhibited by forskolin pretreatment. Rolipram $(1&10{\mu}M)$, a phosphodiesterase inhibitor, did not affect the evoked NE release but reduced the CPA effect. And 8-bromo-cAMP $(100&300{\mu}M)$, a membrane permeable cAMP analogue inhibited the CPA effect significantly. These results suggest that the $A_1-adenosine$ heteroreceptor plays an important role in NE-release via nucleotide-binding protein $G_i$ in the rat hippocampus and that the adenylate cyclase system might be participated in this process.

• The Korean Journal of Physiology and Pharmacology
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• 제14권3호
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• pp.145-150
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• 2010

Adenosine (Ado) is an important mediator of the endogenous defense against ischemia-induced injury in the heart. The action of Ado is mediated by activation of G protein-gated inwardly rectifying $K^+$ (GIRK) channels. In turn, GIRK channels are inhibited by reducing phosphatidylinositol 4,5-bisphosphate ($PIP_2$) through Gq protein-coupled receptors (GqPCRs). We previously found that GIRK channels activated by acetylcholine, a muscarinic M2 acetylcholine receptor agonist, are inhibited by GqPCRs in a receptor-specific manner. However, it is not known whether GIRK channels activated by Ado signaling are also regulated by GqPCRs. Presently, this was investigated in mouse atrial myocytes using the patch clamp technique. GIRK channels were activated by $100\;{\mu}M$ Ado. When Ado was repetitively applied at intervals of 5~6 min, the amplitude of second Ado-activated GIRK currents ($I_{K(Ado)}$) was $88.3{\pm}3.7%$ of the first $I_{K(Ado)}$ in the control. Pretreatment of atrial myocytes with phenylephrine, endothelin-1, or bradykinin prior to a second application of Ado reduced the amplitude of the second $I_{K(Ado)}$ to $25.5{\pm}11.6%$, $30.5{\pm}5.6%$, and $96.0{\pm}2.7%$, respectively. The potency of $I_{K(Ado)}$ inhibition by GqPCRs was different with that observed in acetylcholine-activated GIRK currents ($I_{K(ACh)}$) (endothelin-1>phenylephrine>bradykinin). $I_{K(Ado)}$ was almost completely inhibited by $500\;{\mu}M$ of the $PIP_2$ scavenger neomycin, suggesting low $PIP_2$ affinity of $I_{K(Ado)}$. Taken together, these results suggest that the crosstalk between GqPCRs and the Ado-induced signaling pathway is receptor-specific. The differential change in $PIP_2$ affinity of GIRK channels activated by Ado and ACh may underlie, at least in part, their differential responses to GqPCR agonists.

• The Korean Journal of Physiology and Pharmacology
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• 제1권2호
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• pp.135-142
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• 1997

As it has been reported that the depolarization-induced norepinephrine (NE) release is modulated by activation of presynaptic $A_1$-adenosine heteroreceptor and various lines of evidence indicate that $A_2$-adenosine receptor also presents in hippocampus, and that the adenosine effect is magnesium dependent, the present study was undertaken to delineate the role of adenosine receptors in the modulation of hippocampal NE release. Slices from the rat hippocampus were equilibrated with $[^3H]-NE$ and the release of the labelled product, $[^3H]-NE$, was evoked by electrical stimulation (3 Hz, 5 V $cm^{-1}$, 2 ms, rectangular pulses), and the influence of various agents on the evoked tritium outflow was investigated. $N^6-cyclo-pentyladenosine$ (CPA), in concentrations ranging from 0.1 to 10 ${\mu}M$, decreased the $[^3H]-NE$ release in a dose-dependent manner without changing the basal rate of release, and these effects were significantly inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 ${\mu}M$) treatment. When the magnesium concentration was reduced to 0.4 mM or completely removed, the evoked NE release increased along with decreased basal rate of release. In contrast, increasing the magnesium concentrations to 2.4 and 4 mM, decreased the evoked NE release. The CPA effects on evoked NE release were reducedby magnesium removal, but potentiated by 2.4 mM magnesium in the medium. 5-(N-cyclopropyl)-carboxamodiadenosine (CPCA, 1 & 10 ${\mu}M$), an $A_2$-agonist, decreased the evoked tritium outflow, and this effect was also abolished by DPCPX pretreatment. CGS, a powerful $A_2$-agonist, did not affect the evoked NE release. However, the effects of CPCA and CGS on evoked NE release were significantly increased by pretreatment of DPCPX in the magnesium-free medium. These results indicate that inhibitory effect of $A_1$-adenosine receptor on NE release is magnesium-dependent, and $A_2$-receptor may be present in the rat hippocampus.

• Biomolecules & Therapeutics
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• 제20권1호
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• pp.27-35
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• 2012

Oroxylin A is a flavone isolated from a medicinal herb reported to be effective in reducing the inflammatory and oxidative stresses. It also modulates the production of brain derived neurotrophic factor (BDNF) in cortical neurons by the transactivation of cAMP response element-binding protein (CREB). As a neurotrophin, BDNF plays roles in neuronal development, differentiation, synaptogenesis, and neural protection from the harmful stimuli. Adenosine $A2_A$ receptor colocalized with BDNF in brain and the functional interaction between $A2_A$ receptor stimulation and BDNF action has been suggested. In this study, we investigated the possibility that oroxylin A modulates BDNF production in cortical neuron through the regulation of $A2_A$ receptor system. As expected, CGS21680 ($A2_A$ receptor agonist) induced BDNF expression and release, however, an antagonist, ZM241385, prevented oroxylin A-induced increase in BDNF production. Oroxylin A activated the PI3K-Akt-GSK-$3{\beta}$ signaling pathway, which is inhibited by ZM241385 and the blockade of the signaling pathway abolished the increase in BDNF production. The physiological roles of oroxylin A-induced BDNF production were demonstrated by the increased neurite extension as well as synapse formation from neurons. Overall, oroxylin A might regulate BDNF production in cortical neuron through $A2_A$ receptor stimulation, which promotes cellular survival, synapse formation and neurite extension.

• 한국미생물·생명공학회지
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• 제34권4호
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• pp.289-298
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• 2006

3',5'-cyclic adenosine monophosphate (cAMP) is an important molecule, which mediates diverse cellular processes. For example, it is involved in regulation of sugar uptake/catabolism, DNA replication, cell division, and motility in various acterial species. In addition, cAMP is one of the critical regulators for syntheses of virulence factors in many pathogenic bacteria. It is believed that cAMP acts as a signal for environmental changes as well as a regulatory factor for gene expressions. Therefore, intracellular concentration of cAMP is finely modulated by according to its rates of synthesis (by adenylate cyclase), excretion, and degradation (by cAMP phosphodiesterase). In the present review, we discuss the bacterial physiological characteristics governed by CAMP and the molecular mechanisms for gene regulation by cAMP. Furthermore, the effect of cAMP on phosphotransferase system is addressed.

• Bulletin of the Korean Chemical Society
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• 제26권10호
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• pp.1503-1504
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• 2005

• The Korean Journal of Physiology
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• 제22권2호
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• pp.319-332
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• 1988

The regulations of renal function and renin release are influenced by neural, humoral and physical factors. During the last decade, considerable progress has been made in the identification and characterization of these extrinsic renal control systems. Mechanisms intrinsic to the kidney are also important for renal function. These include the autoregulation of blood flow, and the local control of renin secretion. Fundamental questions regarding the mechanism of these intrinsic controls remain unanswered. Recently, endogenous renal adenosine has been claimed to influence the tubuloglomerular feedback control and renin release. Two subclasses of adenosine receptors $A_1{\;}and{\;}A_2$ have been described. The present experiment was carried out to evaluate the effects of $N_6-cyclohexyladenosine$ $(CHA,{\;}A_1{\;}selective)$ and 5'-N-ethylcarbox-amide adenosine $(NECA,{\;}A_2{\;}selective)$ on the renal function and renin release in the unanesthetized rabbit. Intra-renal arterial infusion of NECA $(0.3{\sim}10.0n{\;}mole/min/rabbit)$ or CHA $(0.03{\sim}10.0n{\;}mole/min/rabbit)$ caused a prompt and dose-dependent decrease in urine volume, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF), electrolyte excretion and free water clearance $(CH_2O)$, the effect being much more profound with CHA than with NECA. The NECA infusion resulted in a profound decrease of systemic blood pressure, but the CHA infusion did not. Both NECA and GHA infusions caused a prompt and dose-dependent decrease in renin secretion rate, again the effect being greater with CHA than with NEGA. These results suggest that both $A_1{\;}and{\;}A_2$ adenosine receptors may be involved in the intrinsic control of renal function and renin release, and that the $A_1$ receptors plays a more important role than the $A_2$ receptor in the regulation of renal fnction.

• Journal of Applied Biological Chemistry
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• 제62권4호
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• pp.425-431
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• 2019

Platelet activation is essential for hemostatic process on blood vessel damage. However, excessive platelet activation can cause some cardiovascular diseases including atherosclerosis, thrombosis, and myocardial infarction. Scoparone is commonly encountered in the roots of genus Artemisia or Scopolia, and has been studied for its potential pharmacological properties including immunosuppression and vasorelaxation, but antiplatelet effects of scoparone have not been reported yet. We investigated the effect of scoparone on human platelet activation prompted by an analogue of thromboxane A₂, U46619. As the results, scoparone dose-dependently increased cyclic adenosine monophosphate (cAMP) levels as well as cyclic guanosine monophosphate (cGMP) levels, both being aggregation-inhibiting molecules. In addition, scoparone strongly phosphorylated inositol 1, 4, 5-triphosphate receptor (IP3R) and vasodilator-stimulated phosphoprotein (VASP), substrates of cAMP dependent kinase and cGMP dependent kinase. Phosphorylation of IP₃R by scoparone resulted in inhibition of Ca²⁺ mobilization in calcium channels in a dense tubular system, and phosphorylation of VASP by scoparone led to an inability of fibrinogen being able to bind to αIIb/β3. Finally, scoparone inhibited thrombin-induced fibrin clotting, thereby reducing thrombus formation. Therefore, we suggest that scoparone has a strong antiplatelet effect and is highly probable to prevent platelet-derived vascular disease.

• The Korean Journal of Physiology and Pharmacology
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• 제3권1호
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• pp.53-57
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• 1999

The activities of myocardial antioxidant enzymes are known to increase in the hearts preconditioned with the brief episodes of ischemia. This study was undertaken to elucidate the possible involvement of adenosine in the stimulation of myocardial catalase induced by the brief regional ischemia in rabbit hearts. Coronary artery descending the middle anterior wall of left ventricle was occluded for 15 min, followed by 1 hr of reperfusion. Upon reperfusion after the brief ischemia, the activity of catalase increased significantly in both ischemic and non-ischemic parts of myocardium. Pretreatment of the heart with theophylline, a non-specific adenosine receptor blocker, completely abolished the increase of catalase activity in both the ischemic and non-ischemic regions of myocardium. On the other hand, the administration of exogenous adenosine instead of the ischemia failed to increase the catalase activity in in vivo hearts. Moreover, adenosine infusion did not affect the catalase activity in the isolated, perfused hearts either. These results suggest that the endogenous adenosine released from the ischemic myocardium is involved in the activation of catalase induced by brief ischemia, but that adenosine may not be a final direct activator of cellular catalase in the myocardium.

• 대한약리학회지
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• 제29권2호
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• pp.253-261
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• 1993

Streptozotocin으로 당뇨병을 유발시킨 흰쥐를 모델로 하여 당뇨병으로 인한 인슐린의 antilipolytic action을 매개하는 insulin-sensitive cyclic nucleotide phosphodiesterase의 역할의 변화 가능성을 연구하였다. 흰쥐의 epididymal adipose tissue로부터 분리한 지방세포를 여러 약물과 toxin으로 전처치한 다음, insulin을 처치 또는 처치하지 않고 $37^{\circ}C$에서 15분 동안 incubation하였다. 그리고 나서 differential centrifugation으로 3 fractions로 분리한 다음 cAMP phosphodiesterase activity를 assay하였다. Insulin에 의한 PDE activities의 증가는 당뇨병군과 대조군 모두 crude microsomal (P2) fraction에서만 볼 수 있었다. P2 fraction을 2 nM insulin, $100\;{\mu}M$ isoproterenol, 또는 두 약물을 함께 처치하여 나타난 maximal effect는 두 군 모두에서 유의한 차이가 없었다. 그러나 basal PDE activities는 당뇨병균이 대조군에 비해 증가한 것으로 나타났다. 당뇨병군의 P2 fraction의 insulin-sensitive PDE activities는 $A_{1}$ adenosine receptor agonist 인 PIA에 의해서 영향을 받지 않은 반면, 대조군의 경우 PIA에 의해 basal PDE activities와 같게 감소하였다. 그리고 지방세포의 pertussis toxin에 대한 sensitivity는 당뇨병군이 대조군보다 더욱 민감하였다. 그러나 cholera toxin에 대한 sensitivity는 당뇨병군과 대조군 사이에 큰 차이를 볼 수 없었다. 이러한 결과로 보아 streptozotocin으로 당뇨병을 유발시킨 흰쥐의 지방세포에서, adenosine receptor와 같은 inhibitory receptor를 경유한 signalling의 감소는 $G_{i}$ proteins의 소실 또는 기능의 감소와 관련이 있으며, 또한 basal state에서 insulin-dependent PDE의 활성을 증가시키는 것으로 사료된다.