Heterologous supersensitization between serotonin2 and alpha2-adrenergic receptor-mediated intracellular calcium mobilization in human platelets
TL;DR: The results suggest that the supersensitization was caused from intracellular Ca2+ storage sites through a G protein-coupled pathway.
Abstract: Recent reports suggest that serotonin (5-HT)2 receptor-mediated second messenger systems are enhanced in platelets of affective disorders. To make the mechanism of the enhanced response clear, we investigated 5-HT2 and alpha (α)2-adrenergic receptor-induced intracellular calcium (Ca2+) mobilization in platelets of healthy volunteers, using fura-2. 5-HT2 and α2-adrenergic receptor-mediated Ca2+ mobilization was enhanced by prior exposure to the other type of agonist, so called “heterologous supersensitization”. The supersensitization was due to the enhancement of maximal response without change in agonist affinity. Chelating extracellular Ca2+ did not diminish the supersensitization. This enhancement of Ca2+ mobilization was not inhibited by H-7, an inhibitor of protein kinase C. However, this supersensitization was inhibited by pretreatment with sodium fluoride which directly activates guanine nucleotide binding regulatory proteins (G proteins). These results suggest that the supersensitization was caused from intracellular Ca2+ storage sites through a G protein-coupled pathway.
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TL;DR: Site-directed mutagenesis of non-conserved amino acids in the second intracellular loop of the α2A subtype indicated that several residues are involved in the coupling specificity, and biphasic dose-response curve could be seen, suggesting that this loop is important for determining the subtype-specific coupling of α2-ARs to cAMP production.
51 citations
Patent•
15 Mar 2007TL;DR: Pyridinone as mentioned in this paper is a positive allosteric modulator of metabotropic receptors -sub-type 2 ("mGluR2") which is useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction.
Abstract: The present invention relates to novel compounds, in particular novel pyridinone de- rivat ives according to Formula (I) wherein all radicals are defined in the application and claims The compounds accord- ing to the invention are positive allosteric modulators of metabotropic receptors - sub- type 2 ("mGluR2") which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy The invention is also directed to pharmaceutical composit ions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved
37 citations
Journal Article•
TL;DR: An enhanced intracellular Ca2+ rise in response to 5-HT in platelets from both bipolar patients and patients with major depression is found.
Abstract: In this report we have investigated the intracellular calcium (Ca2+) mobilization mediated by serotonin 5-HT2A receptors in the platelets of 13 patients with bipolar disorder and 12 patients with major depression in comparison with 15 healthy control subjects. We found an enhanced intracellular Ca2+ rise in response to 5-HT in platelets from both bipolar patients and patients with major depression. The 5-HT2A receptor-mediated intracellular Ca2+ signaling mechanism may have an important role in the pathophysiology of affective disorders.
35 citations
Patent•
12 Nov 2008TL;DR: In this article, a positive allosteric modulator of metabotropic receptors-subtype 2 ('mGluR2') which is useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGlu receptor is involved.
Abstract: The present invention relates to novel compounds, in particular novel imidazo[1,2- a]piridine derivatives according to Formula (I). The compounds according to the invention are positive allosteric modulators of metabotropic receptors- subtype 2 ('mGluR2') which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.
29 citations
Patent•
11 May 2010TL;DR: In this paper, a triazolo[4,3-a]pyridine derivatives of Formula (I) were described, where all radicals are defined as defined in the claims.
Abstract: The present invention relates to novel triazolo[4,3-a]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.
28 citations
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TL;DR: A new family of highly fluorescent indicators has been synthesized for biochemical studies of the physiological role of cytosolic free Ca2+ using an 8-coordinate tetracarboxylate chelating site with stilbene chromophores that offer up to 30-fold brighter fluorescence.
21,582 citations
TL;DR: The alpha subunit of a newly discovered pertussis toxin-insensitive G protein (Gq) has recently been isolated and is shown to stimulate the activity of polyphosphoinositide-specific phospholipase C (PI-PLC) from bovine brain, identifying Gq as a G protein that regulates PI-P LC.
Abstract: The hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C yields the second messengers inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol. This activity is regulated by a variety of hormones through G protein pathways. However, the specific G protein or proteins involved has not been identified. The alpha subunit of a newly discovered pertussis toxin-insensitive G protein (Gq) has recently been isolated and is now shown to stimulate the activity of polyphosphoinositide-specific phospholipase C (PI-PLC) from bovine brain. Both the maximal activity and the affinity of PI-PLC for calcium ion were affected. These results identify Gq as a G protein that regulates PI-PLC.
847 citations
TL;DR: The data strongly suggest that the IAP substrate is another dimeric, guanine nucleotide-binding regulatory protein and that it is responsible for inhibitory modulation of adenylate cyclase activity.
378 citations
TL;DR: This study confirms that fluoride activation of transducin results from a reversible binding of the metal‐fluoride complex in the nucleotide site of T alpha, next to the beta phosphate of GDP, as an analogue of the gamma phosphate.
Abstract: Fluoride activation of G proteins requires the presence of aluminium or beryllium and it has been suggested that AIF4- acts as an analogue of the gamma-phosphate of GTP in the nucleotide site. We have investigated the action of AIF4- or of BeF3- on transducin (T), the G protein of the retinal rods, either indirectly through the activation of cGMP phosphodiesterase, or more directly through their effects on the conformation of transducin itself. In the presence of AIF4- or BeF3-, purified T alpha subunit of transducin activates purified cyclic GMP phosphodiesterase (PDE) in the absence of photoactivated rhodopsin. Activation is totally reversed by elution of fluoride or partially reversed by addition of excess T beta gamma. Activation requires that GDP or a suitable analogue be bound to T alpha: T alpha-GDP and T alpha-GDP alpha S are activable by fluorides, but not T alpha-GDP beta S, nor T alpha that has released its nucleotide upon binding to photoexcited rhodopsin. Analysis of previous works on other G proteins and with other nucleotide analogues confirm that in all cases fluoride activation requires that a GDP unsubstituted at its beta phosphate be bound in T alpha. By contrast with alumino-fluoride complexes, which can adopt various coordination geometries, all beryllium fluoride complexes are tetracoordinated, with a Be-F bond length of 1.55 A, and strictly isomorphous to a phosphate group. Our study confirms that fluoride activation of transducin results from a reversible binding of the metal-fluoride complex in the nucleotide site of T alpha, next to the beta phosphate of GDP, as an analogue of the gamma phosphate.(ABSTRACT TRUNCATED AT 250 WORDS)
365 citations
TL;DR: The inhibitory and stimulatory guanine nucleotide-binding regulatory components (Gi and Gs) of adenylate cyclase both have an alpha X beta subunit structure, and the beta (35,000 Da) and 41,000-Da subunits are functionally indistinguishable.
325 citations