Up-regulation of type II adenylyl cyclase mRNA in kindling model of epilepsy in rats

Iwasa, Hiroto; Kikuchi, Shuichi; Mine, Seiichiro; Miyagishima, Hiro; Sugita, Katsuo; Sato, Toshio; Hasegawa, Shuji

doi:10.1016/s0304-3940(00)00897-1

Cited by 14 publications

(8 citation statements)

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“…AC2 is expressed in brain (Matsuoka et al 1997;Mons et al 2004), and specific signal transduction roles of AC2 have been proposed (Iwasa et al 2000;Näsman et al 2002;Nguyen and Watts 2006;Schallmach et al 2006). Similarly, we cannot yet define a specific role of AC5 in LND, this AC5 being upregulated at the mRNA level in B103 cells (Table 2).…”

Section: Discussionmentioning

confidence: 88%

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Kinast

Ohe

Burhenne

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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Hypoxanthine phosphoribosyl transferase (HPRT) deficiency results in Lesch-Nyhan disease (LND). The link between the HPRT defect and the self-injurious behavior in LND is still unknown. HPRT-deficient rat B103 neuroblastoma cells serve as a model system for LND. In B103 cell membranes, HPRT deficiency is associated with a decrease of basal and guanosine triphosphate-stimulated adenylyl cyclase (AC) activity (Pinto and Seifert, J Neurochem 96:454-459, 2006). Since recombinant AC2 possesses a high basal activity, we tested the hypothesis that AC2 function and expression is impaired in HPRT deficiency. We examined AC regulation in B103 cell membranes, cAMP accumulation in intact B103 cells, AC isoform expression, and performed morphological studies. As most important pharmacological tool, we used 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene forskolin (BODIPY-FS) that inhibits recombinant AC2 but activates ACs 1 and 5 (Erdorf et al., Biochem Pharmacol 82:1673-1681, 2011). In B103 control membranes, BODIPY-FS reduced catalysis, but in HPRT(-) membranes, BODIPY-FS was rather stimulatory. 2'(3')-O-(N-methylanthraniloyl) (MANT)-nucleoside 5'-[γ-thio]triphosphates inhibit recombinant ACs 1 and 5 more potently than AC2. In B103 control membranes, MANT-guanosine 5'-[γ-thio]triphosphate inhibited catalysis in control membranes less potently than in HPRT(-) membranes. Quantitative real-time PCR revealed that in HPRT deficiency, AC2 was virtually absent. In contrast, AC5 was up-regulated. Forskolin (FS) and BODIPY-FS induced cell clustering and rounding and neurite extension in B103 cells. The effects of FS and BODIPY-FS were much more prominent in control than in HPRT(-) cells, indicative for a differentiation defect in HPRT deficiency. Neither FS nor BODIPY-FS significantly changed cAMP concentrations in intact B103 cells. Collectively, our data show that HPRT deficiency in B103 cells is associated with impaired AC2 function and expression and reduced sensitivity to differentiation induced by FS and BODIPY-FS. We discuss the pathophysiological implications of our data for LND.

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Section: Discussionmentioning

confidence: 88%

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Kinast

Ohe

Burhenne

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…This sensitivity coupled with their expression in bronchial smooth muscle, hippocampus, piriform cortex, spinal cord and olfactory system etc. [10–12] renders them potentially important physiological and therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Muscarinic receptors stimulate AC2 by novel phosphorylation sites, whereas Gβγ subunits exert opposing effects depending on the G-protein source

Shen

Wachten

Halls

et al. 2012

Biochemical Journal

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Direct phosphorylation of AC2 (adenylyl cyclase 2) by PKC (protein kinase C) affords an opportunity for AC2 to integrate signals from non-canonical pathways to produce the second messenger, cyclic AMP. The present study shows that stimulation of AC2 by pharmacological activation of PKC or muscarinic receptor activation is primarily the result of phosphorylation of Ser490 and Ser543, as opposed to the previously proposed Thr1057. A double phosphorylation-deficient mutant (S490/543A) of AC2 was insensitive to PMA (phorbol myristic acid) and CCh (carbachol) stimulation, whereas a double phosphomimetic mutant (S490/543D) mimicked the activity of PKC-activated AC2. Putative Gβγ-interacting sites are in the immediate environment of these PKC phosphorylation sites (Ser490 and Ser543) that are located within the C1b domain of AC2, suggesting a significant regulatory importance of this domain. Consequently, we examined the effect of both Gq-coupled muscarinic and Gi-coupled somatostatin receptors. Employing pharmacological and FRET (fluorescence resonance energy transfer)-based real-time single cell imaging approaches, we found that Gβγ released from the Gq-coupled muscarinic receptor or Gi-coupled somatostatin receptors exert inhibitory or stimulatory effects respectively. These results underline the sophisticated regulatory capacities of AC2, in not only being subject to regulation by PKC, but also and in an opposite manner to Gβγ subunits, depending on their source.

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“…Since the expression level of adenylyl cyclase, the main effector system of adenosine receptors, has been shown to be modulated in kindling model of epilepsy in rats (Iwasa et al . ) we decided to investigate whether mRNA coding adenylyl cyclase type II could be also regulated in response to fever seizures. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Hyperthermia‐induced seizures alter adenosine A₁ and A_2A receptors and 5′‐nucleotidase activity in rat cerebral cortex

León-Navarro

Albasanz

Martı́n

2015

Journal of Neurochemistry

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Febrile seizure is one of the most common convulsive disorders in children. The neuromodulator adenosine exerts anticonvulsant actions through binding adenosine receptors. Here, the impact of hyperthermia-induced seizures on adenosine A 1 and A 2A receptors and 5 0 -nucleotidase activity has been studied at different periods in the cerebral cortical area by using radioligand binding, real-time PCR, and 5 0 -nucleotidase activity assays. Hyperthermic seizures were induced in 13-day-old rats using a warmed air stream from a hair dryer.

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Up-regulation of type II adenylyl cyclase mRNA in kindling model of epilepsy in rats

Cited by 14 publications

References 14 publications

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Muscarinic receptors stimulate AC2 by novel phosphorylation sites, whereas Gβγ subunits exert opposing effects depending on the G-protein source

Hyperthermia‐induced seizures alter adenosine A₁ and A_2A receptors and 5′‐nucleotidase activity in rat cerebral cortex

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Up-regulation of type II adenylyl cyclase mRNA in kindling model of epilepsy in rats

Cited by 14 publications

References 14 publications

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Muscarinic receptors stimulate AC2 by novel phosphorylation sites, whereas Gβγ subunits exert opposing effects depending on the G-protein source

Hyperthermia‐induced seizures alter adenosine A1 and A2A receptors and 5′‐nucleotidase activity in rat cerebral cortex

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Hyperthermia‐induced seizures alter adenosine A₁ and A_2A receptors and 5′‐nucleotidase activity in rat cerebral cortex