Coupling of human α2-adrenoceptor subtypes to regulation of cAMP production in transfected S115 cells

Jansson, Christian; Marjamäki, Anne; Luomala, Kirsti; Savola, Juha‐Matti; Scheinin, Mika; Åkerman, Karl E.O.

doi:10.1016/0922-4106(94)90106-6

Cited by 67 publications

(45 citation statements)

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“…Interestingly, we have observed that mice overexpressing ␣2C-adrenoceptors were re-tarded in developing an effective escape strategy in the water maze, and the involvement of ␣2C-adrenoceptors was supported by altered dose response relationships to an ␣2-antagonist (Björklund et al 1996). Therefore, the increase in working memory errors and slowing of effortful mental processing by clonidine at the highest dose tested may be related to stronger activation of ␣2C-adrenoceptors by 5 g/kg clonidine than that attained with 29 g/kg guanfacine (Jansson et al 1994). Furthermore, an additional possibility is that at the doses used in this study clonidine increases the activity of thalamic ␣2B-adrenoceptors more strongly than guanfacine (Jansson et al 1994;Aantaa et al 1995) and thus is more capable of depressing the speed of effortful information processing.…”

Section: Discussionmentioning

confidence: 90%

Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans

Jäkälä

Riekkinen

Sirviö

et al. 1999

Neuropsychopharmacology

165

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Section: Discussionmentioning

confidence: 90%

Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans

Jäkälä

Riekkinen

Sirviö

et al. 1999

Neuropsychopharmacology

165

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“…Similar ®ndings have also been demonstrated by measuring the coupling of the a 2B -subtype to cyclic AMP-dependent reporter gene expression in transiently transfected JEG-3 cells (Pepperl & Regan, 1993). However, when the a 2B -subtype was expressed in S115 cells, it was able to couple to the stimulation of cyclic AMP production only after the cells had been pre-exposed to pertussis toxin, an e ect not observed with the other two a 2 -adrenoceptor subtypes (Jansson et al, 1994b). In contrast, expression of the a 2B -adrenoceptor in NIH-3T3 cells (Duzic & Lanier, 1992), CHO cells (Eason et al, 1992), astroglia cells (Enkvist et al, 1996), DDT 1 MF-2 cells (Duzic & Lanier, 1992), and NG108-15 cells (Sabol & Nirenberg, 1979) resulted in an inhibitory e ect being observed upon activation of the receptor.…”

Section: Discussionmentioning

confidence: 94%

“…In addition, the fact that the a 2C -subtype is equally coupled to the inhibition and stimulation of cyclic AMP production, is consistent with the idea that its true physiological role may be to modulate the e ects mediated by the other two a 2 -adrenoceptor subtypes (MacDonald et al, 1997). However, it should be noted that when the a 2C -adrenoceptor was expressed in cell types such as Chinese hamster lung ®broblasts, JEG-3 cells and S115 cells, the receptor coupled only to the inhibition of cyclic AMP production when activated by an agonist (Cotecchia et al, 1990;MarjamaÈ ki et al, 1992;Pepperl & Regan, 1993;Jansson et al, 1994b).…”

Section: Discussionmentioning

confidence: 99%

“…See Kukkonen et al, 1998;Peltonen et al, 1998;Pihlavisto et al, 1998;Audubert et al, 1999;Olli-LaÈ hdesmaÈ ki et al, 1999;Prezeau et al, 1999;Takesono et al, 1999). The ability of the three a 2 -adrenoceptor subtypes to regulate the cyclic AMP second messenger pathway, has been extensively studied in numerous cell lines (Duzic & Lanier, 1992;Eason et al, 1992;Jansson et al, 1994b;NaÈ sman et al, 1997;Pohjanoksa et al, 1997). However, a great degree of variability has been observed in the results obtained from these studies, which has been attributed variously to the receptor density, the environment of the cell line and the agonist used.…”

Section: Introductionmentioning

confidence: 99%

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A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes

Rudling

Richardson

Evans

2000

British J Pharmacology

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1 The agonist-speci®c coupling properties of the three cloned human a 2 -adrenoceptor subtypes have been compared, when expressed at similar levels in Chinese hamster ovary (CHO) cell lines, using noradrenaline and (+)-meta-octopamine as agonists. 2 Noradrenaline can couple the receptor to both the inhibition and stimulation of forskolinstimulated cyclic AMP production in all three receptor subtypes, with the relative strength of the coupling to the pathways varying for each of the receptor subtypes. 3 meta-Octopamine selectively couples the a 2A -adrenoceptor only to the inhibition of forskolinstimulated cyclic AMP production. However, meta-octopamine couples the a 2B -and a 2C -adrenoceptors to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production. 4 The relative potency of meta-octopamine to noradrenaline varies between the di erent a 2 -adrenoceptor subtypes. The e ects of meta-octopamine are around two orders of magnitude less potent than those of noradrenaline on both the a 2A -and a 2B -adrenoceptor subtypes. In contrast, in the case of the a 2C -adrenoceptor, meta-octopamine is only one order of magnitude less potent than noradrenaline in the stimulation of forskolin-stimulated cyclic AMP production and, in addition, is equipotent with noradrenaline in the inhibition of forskolin-stimulated cyclic AMP production and has an increased maximal response. This raises the possibility that meta-octopamine may have physiologically important actions via a 2C -adrenoceptors in vivo. 5 The results show that the modulation of cyclic AMP production occurs in both a subtype-and agonist-speci®c manner for a 2A -adrenoceptors and in a subtype speci®c manner for a 2B -and a 2C -adrenoceptors.

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“…The alpha2A-C10/ alpha2B-C2 Ki value ratios of clonidine and guanfacine were nearly equal. On the contrary, alpha2A-C10 versus alpha2C-C4 Ki value ratio of clonidine was 0.08 and that of guanfacine 0.04, indicating that guanfacine has a somewhat higher selectivity for alpha2A-adrenoceptor subtype than clonidine (Jansson et al 1994).In humans, alpha2-adrenergic drugs can modulate several forms of attentional functions. In sustained attention tasks, clonidine impairs performance (Coull et al 1995a; Jäkälä et al in press).…”

mentioning

confidence: 92%

Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans

Jäkälä

1999

Neuropsychopharmacology

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The present study compares the effects of two clonidine (0.5, 2, and 5 g/kg, PO) and guanfacine (7 and 29 g/kg, PO) The locus coeruleus (LC) noradrenergic system plays an important role in arousal, vigilance, responses to novel, salient stimuli as well as several aspects of attentional functions (Foote and Morrison 1987;Harley 1987;Robbins and Everitt 1987;McCormick 1989;Aston-Jones et al. 1990;Jäkälä et al. 1992;Robbins and Everitt 1994). For example, in electrophysiological studies, noradrenaline regulates cortical desynchronization/synchronization (Riekkinen Jr. et al. 1990;Berridge and Foote 1991;Riekkinen Jr. et al. 1993), increases the signalto-noise ratio (SNR) in the neocortex (Waterhouse et al. 1981;Morrison and Magistretti 1983), regulates the responsivity of thalamo-cortical relay neurons (Buzsáki et al. 1990;Riekkinen Jr. et al. 1991;Riekkinen Jr. et al. 1993), and facilitates excitatory and inhibitory responses in the limbic system (Segal and Bloom 1976;Sara and Bergis 1991). in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests. In the PAL test, clonidine 2 and guanfacine 29 g/kg improvedThe firing rate of LC noradrenergic neurons is regulated by alpha2-adrenergic autoreceptors (Aghajanian et al. 1977; Aghajanian and VanderMaelen 1982). Activation of these receptors by alpha2-agonists causes autoinhibition of noradrenergic neurons and a reduction in central noradrenergic activity (Cederbaum and Agha- Prichard et al. 1979; Aoki et al. 1994;Scheinin et al 1994;Rosin et al. 1996).Three subtypes of alpha2-adrenoceptors (alpha2A, alpha2B, and alpha2C) have been cloned in humans (Kobilka et al. 1987;Regan et al. 1988;Lomasney et al. 1990). The anatomical distribution of the subtypes is unique MacDonald et al. 1997), suggesting that modulation of these subtypes by subtype selective ligands might be of therapeutic importance. Unfortunately, no such subtype selective ligands are currently available. However, the adverse effects (sedation, hypotension) of unselective alpha2-agonists could be dissociated from their beneficial (cognitionenhancing) effects based on their relative affinities for each receptor subtype. Indeed, in the rat brain, alpha2B messanger (m) RNA is found exclusively in the thalamus , and an action at this receptor subtype could impair thalamocortical arousal mechanisms (Riekkinen, Jr. et al. 1993). The brainstem nucleus tractus solitarius contains alpha2A and alpha2C mRNA, and recently, action at the alpha2A adrenoceptor subtype was shown to mediate the hypotensive effects of alpha2-agonists (MacMillan et al. 1996). In the monkey prefrontal cortex, the alpha2A subtype has the densest distribution of all three alpha2-adrenoceptor subtypes (Aoki et al. 1994). Importantly, in monkeys, the ability of subtype nonselective alpha2-agonists, such as clonidine and guanfacine, to improve prefrontal cortical functions, such as spatial working memory performance, without causin...

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Coupling of human α2-adrenoceptor subtypes to regulation of cAMP production in transfected S115 cells

Cited by 67 publications

References 25 publications

Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans

Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans

A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes

Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans

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Coupling of human α2-adrenoceptor subtypes to regulation of cAMP production in transfected S115 cells

Cited by 67 publications

References 25 publications

Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans

Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans

A comparison of agonist‐specific coupling of cloned human α2‐adrenoceptor subtypes

Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans

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A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes