Adenylyl cyclases and the interaction between calcium and cAMP signalling

Cooper, Dermot M.F.; Mons, Nicole; Karpen, Jeffrey W.

doi:10.1038/374421a0

Cited by 576 publications

(425 citation statements)

References 60 publications

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“…Abnormalities of the cAMP-PKA signaling cascade have also been implicated in the pathophysiology of BD and as a target of lithium action (Perez et al, 2000;Chang et al, 2002). Furthermore, the cAMP system is, in turn, subject to cross-regulation by Ca 2 þ signaling through regulation at a variety of points in the cAMP signaling cascade (Choi et al, 1993;Cooper et al, 1995). Thus, it may be that multiple actions of lithium on diverse signal transduction systems are essential to its therapeutic efficacy in BD.…”

Section: Discussionmentioning

confidence: 99%

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Wasserman

Corson

Sibony

et al. 2004

Neuropsychopharmacol

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Elevated basal intracellular calcium (Ca 2 þ ) levels ([Ca 2 þ ] B ) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca 2 þ homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca 2 þ signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca 2 þ homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N ¼ 26) and healthy subjects (N ¼ 17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca 2 þ ] B , lysophosphatidic acid (LPA)-stimulated Ca 2 þ mobilization ([Ca 2 þ ] S ), and thapsigargin-induced store-operated Ca 2 þ entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca 2 þ ] B (F ¼ 8.47; p ¼ 0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca 2 þ ] S and SOCE were significantly reduced (F ¼ 11.1, p ¼ 0.002 and F ¼ 8.36, p ¼ 0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca 2 þ ] B in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca 2 þ mobilization in BLCLs suggests that modulation of intracellular Ca 2 þ homeostasis may be important to the therapeutic action of lithium.

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Section: Discussionmentioning

confidence: 99%

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Wasserman

Corson

Sibony

et al. 2004

Neuropsychopharmacol

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“…Similarly, in cells expressing ACI, which is activated by calcium͞calmodulin, alterations in cellular calcium concentrations increase cAMP accumulation (ref. 34; also for review, see 35). Since ACV and ACVI are two of the most prominent forms of AC expressed in the heart (6-9) and because oscillations in cAMP concentration in the heart have been reported to occur during cardiac contractions (36), it is tempting to speculate that the inhibition of ACV and ACVI by Ca 2ϩ may serve as a negative feedback to inhibit enzyme activity and reduce cAMP levels during a contraction.…”

Section: Resultsmentioning

confidence: 99%

Characterization of soluble forms of nonchimeric type V adenylyl cyclases

Scholich

Barbier

Mullenix

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Type V adenylyl cyclase (ACV) belongs to the family of Ca 2+ - inhibited cyclases. We have generated two soluble forms of the enzyme containing the C1 or C1a region (which lacks the C-terminal 112 amino acids) linked to the C2 domain and compared their regulation with the full-length ACV. All three forms of ACV were stimulated by the α subunit of the stimulatory G protein G s (G sα ) and forskolin. However, the synergistic stimulation by both these activators was markedly enhanced in the soluble enzymes. Moreover, the α subunit of the inhibitory G protein G i (G iα ) inhibited all forms of the enzyme, indicating that the regions for G sα and G iα interaction are preserved in the soluble forms. Ca 2+ inhibited forskolin-stimulated adenylyl cyclase (AC) activity of the full-length and C1-C2 forms of ACV but did not alter the activity of the C1a-C2 form. Maximal stimulation of AC activity by combination of G sα and forskolin obliterated the Ca 2+ -mediated inhibition of the full-length and C1-C2 forms of ACV. In 45 Ca 2+ overlay experiments, the C1-C2 but not the C1a-C2 soluble ACV bound Ca 2+ . Moreover, proteins corresponding to the C1a and C2 domains did not bind calcium. On the other hand, the proteins corresponding to C1 and its C-terminal 112 amino acids (C1b) bound 45 Ca 2+ . To our knowledge, this is the first report of nonchimeric soluble forms of AC in which regulation by G sα and G iα is preserved. Moreover, we demonstrate that the 112 amino acid C1b region of ACV is responsible for the binding of Ca 2+ and inhibition of enzyme activity.

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“…It is blocked in the presence of the ␤ARK1-CT fusion protein, which selectively binds G ␤␥ -subunits in other preparations (Inglese et al, 1993(Inglese et al, , 1995Boekhoff et al, 1994;Koch et al, 1994). Previous studies have shown a G ␤␥ -subunit-mediated stimulation of the type II and type IV forms of adenylyl cyclase activity (Cooper et al, 1995). Another Drosophila D1-like receptor has been cloned and expressed in various mammalian cell lines and shown to activate adenylyl cyclase (Gotzes et al, 1994;Sugamori et al, 1995), but nothing is known about its mechanism of adenylyl cyclase activation or of its ability to couple directly or indirectly to multiple second messenger pathways.…”

Section: Discussionmentioning

confidence: 99%

“…However, in many cell types the type II and type IV forms of adenylyl cyclase activity can be stimulated by the ␤␥ subunits of G-proteins, in addition to G ␣s (Cooper et al, 1995). Thus, to see whether ␤␥ subunits are involved in the dopaminemediated increases in oocyte cAMP levels in oocytes expressing the DopR99B receptor, we have compared the effects of dopamine in the presence and absence of injections of a ␤ARK1-CT GST fusion protein.…”

Section: G-protein Couplingmentioning

confidence: 99%

Agonist-Specific Coupling of a ClonedDrosophila melanogasterD1-Like Dopamine Receptor to Multiple Second Messenger Pathways by Synthetic Agonists

et al. 1997

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The mechanism of coupling of a cloned Drosophila D1-like dopamine receptor, DopR99B, to multiple second messenger systems when expressed in Xenopus oocytes is described. The receptor is coupled directly to the generation of a rapid, transient intracellular Ca 2ϩ signal, monitored as changes in inward current mediated by the oocyte endogenous Ca 2ϩ -activated chloride channel, by a pertussis toxin-insensitive G-proteincoupled pathway. The more prolonged receptor-mediated changes in adenylyl cyclase activity are generated by an independent G-protein-coupled pathway that is pertussis toxinsensitive but calcium-independent, and G ␤␥ -subunits appear to be involved in the transduction of this response. This is the first evidence for the direct coupling of a cloned D1-like dopamine receptor both to the activation of adenylyl cyclase and to the initiation of an intracellular Ca 2ϩ signal. The pharmacological profile of both second messenger effects is identical for a range of naturally occurring catecholamine ligands (dopamine Ͼ norepinephrine Ͼ epinephrine) and for the blockade of dopamine responses by a range of synthetic antagonists. However, the pharmacological profiles of the two second messenger responses differ for a range of synthetic agonists. Thus, the receptor exhibits agonist-specific coupling to second messenger systems for synthetic agonists. This feature could provide a useful tool in the genetic analysis of the roles of the multiple second messenger pathways activated by this receptor, given the likely involvement of dopamine in the processes of learning and memory in the insect nervous system.

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Adenylyl cyclases and the interaction between calcium and cAMP signalling

Cited by 576 publications

References 60 publications

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Characterization of soluble forms of nonchimeric type V adenylyl cyclases

Agonist-Specific Coupling of a ClonedDrosophila melanogasterD1-Like Dopamine Receptor to Multiple Second Messenger Pathways by Synthetic Agonists

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