Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S100B is a calcium-binding protein with both extracellular and intracellular regulatory activities in the mammalian brain. We have identified a novel interaction between S100B and the dopamine D(2) receptor. Our results also suggest that the binding of S100B to the dopamine D(2) receptor enhances receptor signaling. This conclusion is based on the following observations: 1) S100B and the third cytoplasmic loop of the dopamine D(2) receptor interact in a bacterial two-hybrid system and in a poly-histidine pull-down assay; 2) immunoprecipitation of the D(2) receptor also precipitates FLAG-S100B from human embryonic kidney 293 cell homogenates and endogenous S100B from rat neostriatal homogenates; 3) S100B immunoreactivity was detected in cultured neostriatal neurons expressing the D(2) receptor; 4) a putative S100B binding motif is located at residues 233 to 240 of the D(2) receptor, toward the amino terminus of the third cytoplasmic loop. D(3)-IC3, which does not bind S100B, does not contain this motif; and 5) coexpression of S100B in D(2) receptor-expressing 293 cells selectively increased D(2) receptor stimulation of extracellular signal-regulated kinases and inhibition of adenylate cyclase.
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PMID:Novel interaction of the dopamine D2 receptor and the Ca2+ binding protein S100B: role in D2 receptor function. 1851 53

Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes.
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PMID:In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants. 2151 66

This monograph presents a historical perspective of cornerstone developments on the biochemistry and physiology of mammalian membrane guanylate cyclases (MGCs), highlighting contributions made by the authors and their collaborators. Upon resolution of early contentious studies, cyclic GMP emerged alongside cyclic AMP, as an important intracellular second messenger for hormonal signaling. However, the two signaling pathways differ in significant ways. In the cyclic AMP pathway, hormone binding to a G protein coupled receptor leads to stimulation or inhibition of an adenylate cyclase, whereas the cyclic GMP pathway dispenses with intermediaries; hormone binds to an MGC to affect its activity. Although the cyclic GMP pathway is direct, it is by no means simple. The modular design of the molecule incorporates regulation by ATP binding and phosphorylation. MGCs can form complexes with Ca²⁺-sensing subunits that either increase or decrease cyclic GMP synthesis, depending on subunit identity. In some systems, co-expression of two Ca²⁺ sensors, GCAP1 and S100B with ROS-GC1 confers bimodal signaling marked by increases in cyclic GMP synthesis when intracellular Ca²⁺ concentration rises or falls. Some MGCs monitor or are modulated by carbon dioxide via its conversion to bicarbonate. One MGC even functions as a thermosensor as well as a chemosensor; activity reaches a maximum with a mild drop in temperature. The complexity afforded by these multiple limbs of operation enables MGC networks to perform transductions traditionally reserved for G protein coupled receptors and Transient Receptor Potential (TRP) ion channels and to serve a diverse array of functions, including control over cardiac vasculature, smooth muscle relaxation, blood pressure regulation, cellular growth, sensory transductions, neural plasticity and memory.
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PMID:Integrative Signaling Networks of Membrane Guanylate Cyclases: Biochemistry and Physiology. 2769 98

Migraine has a strong genetic component and is characterized by multiphasic events including an initial premonitory phase with premonitory symptoms (PS). Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP38) are endogenous neuropeptides that can trigger migraine attacks and have in recent years gained considerable interest in the migraine field. Yet, the exact pathophysiological mechanisms underlying CGRP- and PACAP38-induced attacks are not fully clarified. Human provocation models have shown that these peptides induce attacks in only two- thirds of migraine patients. Whether this diverse migraine response after CGRP or PACAP38 may be explained by genetic factors is unknown. The present thesis includes four studies that explore different factors that may be associated with the CGRP- and PACAP38-induced migraine response. In study I and II we investigated the role of familial predisposition (family load) and number of risk conferring gene variants on migraine attacks induced by CGRP or PA-CAP38. In study III, we investigated biochemical changes of CGRP, vasoactive intestinal peptide (VIP), S100B and TNF-alpha in the blood after PACAP38. Finally in study IV, we studied whether CGRP or PACAP38 may induce PS. Study I and II demonstrated that PACAP38 and CGRP induce migraine attacks in 63% and 72% of the patients, respectively. Moreover, we showed that patients with high family load or a high number of migraine associated gene variants did not report more migraine attacks after CGRP or PACAP38 than those with no familial predisposition or few gene variants. Study III showed that PACAP38 infusion caused changes in plasma concentrations for VIP and S100B, but not CGRP and TNF-alpha, suggesting activation of parasympathetic nerve endings. Study IV showed absence of PS after CGRP and lack of statistical difference in PS between patients who reported and not reported attacks after PACAP38 suggesting peripheral mechanisms of induction. In conclusion, the present thesis suggests that genetics factors such as family load and genetic variants do not contribute to susceptibility of migraine attacks induced by CGRP or PACAP38. Additionally, our data indicate that CGRP and PACAP38 primarily have a peripheral site of action. We believe that the acquired knowledge from this thesis on how CGRP and PACAP38 might be involved in migraine pathophysiology would contribute to the development of novel and better migraine treatments in the future.
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PMID:The role of genetics on migraine induction triggered by CGRP and PACAP38. 2826 Jun 3

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