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Second Messenger Systems (second + messenger_system)
Selected AbstractsMarkedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5GENES, BRAIN AND BEHAVIOR, Issue 2 2007K.-S. Kim Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5,/,). We found that AC5,/, mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5,/, mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5,/, mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain. [source] A review of the possible relevance of inositol and the phosphatidylinositol second messenger system (PI-cycle) to psychiatric disorders,focus on magnetic resonance spectroscopy (MRS) studiesHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2005Hyeonjin Kim Abstract Myo -inositol is an important part of the phosphatidylinositol second messenger system (PI-cycle). Abnormalities in nerve cell myo -inositol levels and/or PI-cycle regulation has been suggested as being involved in the pathophysiology and/or treatment of many psychiatric disorders including bipolar disorder, major depressive disorder, panic disorder, obsessive-compulsive disorder, eating disorders and schizophrenia. This review examines the metabolism and biochemical importance of myo -inositol and the PI-cycle. It relates this to the current in vivo evidence for myo -inositol and PI-cycle involvement in these psychiatric disorders, particularly focusing upon the magnetic resonance spectroscopy (MRS) findings in patient studies to date. From this review it is concluded that while the evidence suggests probable relevance to the pathophysiology and/or treatment of bipolar disorder, there is much less support for a significant role for the PI-cycle or myo -inositol in any other psychiatric disorder. More definitive investigation is required before PI-cycle dysfunction can be considered specific to bipolar disorder. Copyright © 2005 John Wiley & Sons, Ltd. [source] SHORT COMMUNICATION Learning-induced reduction in post-burst after-hyperpolarization (AHP) is mediated by activation of PKCEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2002Yaron Seroussi Abstract We studied the role of protein kinase C (PKC) and protein kinase A (PKA) in mediating learning-related long lasting reduction of the post-burst after-hyperpolarization (AHP) in cortical pyramidal neurons. We have shown previously that pyramidal neurons in the rat piriform (olfactory) cortex from trained (TR) rats have reduced post-burst AHP for 3 days after odour-discrimination learning, and that this reduction is due to decreased conductance of calcium-dependent potassium current. In the present study, we examined whether this long-lasting reduction in AHP is mediated by second messenger systems. The broad-spectrum kinase inhibitor, H7, increased the AHP in neurons from TR rats, but not in neurons from pseudo-trained (pseudo-TR) and naive rats. Consequently, the difference in AHP amplitude between neurons from TR and control animals was diminished. This effect was also obtained by application of the specific PKC inhibitor, GF-109203x. The PKC activator, 1-Oleoyl-2-acetyl- sn -glycerol (OAG), significantly reduced the AHP in neurons from naive and pseudo-TR rats, but not in neurons from TR rats, so that the difference between the groups was abolished. The PKA-specific inhibitor, H-89, increased the AHP in neurons from all groups to a similar extent, and the difference in AHP amplitude between neurons from TR rats and neurons from controls was maintained. We suggest that while the post-burst AHP in piriform cortex pyramidal neurons is modulated by both PKC and PKA, a PKC-dependent process maintains the learning-related reduction of the AHP in these cells. [source] Transgenic Animals in Cardiovascular Disease ResearchEXPERIMENTAL PHYSIOLOGY, Issue 6 2000Michael Bader Worldwide, the highest morbidity and mortality results from such cardiovascular diseases as hypertension, myocardial infarction, cardiac and renal failure, as well as stroke. Since the cardiovascular system and its regulation is quite complex, study of these disorders has been grossly limited to whole organism models. As a result, in recent years, transgenic technology has played a significant role in the discovery of specific gene products for cardiovascular regulation and disease aetiology. Genetic manipulation in rats and mice has altered the expression of numerous genes. In this review, some of the important new genetically modified animals (i.e. transgenic models) with alterations in hormone and second messenger systems involved in cardiovascular regulation are summarized. [source] Regulation of intracellular cyclic GMP levels in olfactory sensory neuronsJOURNAL OF NEUROCHEMISTRY, Issue 1 2005Cheil Moon Abstract Cyclic AMP is the primary second messenger mediating odorant signal transduction in mammals. A number of studies indicate that cyclic GMP is also involved in a variety of other olfactory signal transduction processes, including adaptation, neuronal development, and long-term cellular responses in the setting of odorant stimulation. However, the mechanisms that control the production and degradation of cGMP in olfactory sensory neurons (OSNs) remain unclear. Here, we investigate these mechanisms using primary cultures of OSNs. We demonstrate that odorants increase cGMP levels in intact OSNs in vitro. Different from the rapid and transient cAMP responses to odorants, the cGMP elevation is both delayed and sustained. Inhibition of soluble guanylyl cyclase and heme oxygenase blocks these odorant-induced cGMP increases, whereas inhibition of cGMP PDEs (phosphodiesterases) increases this response. cGMP PDE activity is increased by odorant stimulation, and is sensitive to both ambient calcium and cAMP concentrations. Calcium stimulates cGMP PDE activity, whereas cAMP and protein kinase A appears to inhibit it. These data demonstrate a mechanism by which odorant stimulation may regulate cGMP levels through the modulation of cAMP and calcium level in OSNs. Such interactions between odorants and second messenger systems may be important to the integration of immediate and long-term responses in the setting odorant stimulation. [source] Antioxidants, vitamin C and dithiothreitol, activate membrane-bound guanylate cyclase in PC12 cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2001Zi-Jiang Chen Antioxidants and antioxidant enzymes are known to protect against cell death induced by reactive oxygen species. However, apart from directly quenching free radicals, little is known about the effect of antioxidants on hormone-activated second messenger systems. We previously found that antioxidants such as 17-, estradiol and resveratrol activate membrane-bound guanylate cyclase GC-A, the receptor for atrial natriuretic factor (ANF), in PC12 cells. It is possible that other antioxidants may also activate membrane-bound guanylate cyclase GC-A. The aim of this study was to determine if dithiothreitol (DTT), vitamin C, and vitamin E activate membrane-bound guanylate cyclase GC-A in PC12 cells. The results showed that both DTT and vitamin C increased cGMP levels in PC12 cells, whereas vitamin E had no effect. DTT and vitamin C inhibited membrane-bound guanylate cyclase activity stimulated by ANF in PC12 cells. In contrast, DTT and vitamin C had no effect on soluble guanylate cyclase activity stimulated by substance P. Furthermore, NO synthase inhibitors L-NAME and aminoguanidine did not affect DTT- and vitamin C-stimulated guanylate cyclase activity. The results indicate that DTT and vitamin C, but not vitamin E, activate membrane-bound guanylate cyclase GC-A in PC12 cells. [source] Haemodynamic action of B-type natriuretic peptide substantially outlasts its plasma half-life in conscious dogsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2003Colleen J Thomas Summary 1.,The objective of the present study was to determine the plasma half-life of B-type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP-32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained. 2.,Baseline plasma BNP levels were 15.0 ± 2.3 fmol/mL and rose approximately 10-fold to 159 ± 23 fmol/mL after 20,25 min BNP infusion. When the infusion was turned off, plasma BNP levels declined in a biphasic manner, with an initial half-life of 1.57 ± 0.14 min and a terminal half-life of 301 ± 85 min. The metabolic clearance rate of BNP was 2.29 ± 0.34 L/min. 3.,The infusion of BNP reduced MAP (approximately 10%), CVP (approximately 65%) and MBF (approximately 25%), whereas haematocrit (approximately 4%) and mesenteric vascular resistance (MVR) increased (approximately 40%; all P < 0.05). Plasma BNP levels returned to baseline by 20 min after BNP infusion had been stopped, whereas none of the haemodynamic variables returned to normal by this time. Mean arterial pressure returned to resting levels within 10,15 min after plasma BNP returned to normal. However, CVP, haematocrit and MBF remained substantially below baseline values for more than 20 min after circulating BNP levels had returned to pre-infusion levels. Of these, only mesenteric vascular changes were returned to baseline within 60 min of plasma BNP levels normalizing. 4.,These results demonstrate that the removal of BNP from the canine circulation is rapid, similar to observations made regarding the metabolism of circulating atrial natriuretic peptide in dogs. The half-life of BNP in dogs was shorter than that in rats, sheep or humans. However, the haemodynamic actions of BNP substantially outlasted its plasma half-life. Whether this disparity in plasma level and haemodynamic activity of BNP reflects long-lasting activation of second messenger systems or slow recovery from the hydraulic changes at the capillary level, reflected in the haematocrit and CVP, remains to be answered. [source] | |||||||||||||