Corticotropin-Releasing Factor Receptors Couple to Multiple G-Proteins to Activate Diverse Intracellular Signaling Pathways in Mouse Hippocampus: Role in Neuronal Excitability and Associative Learning

Blank, Thomas; Nijholt, Ingrid M.; Grammatopoulos, Dimitris K.; Randeva, Harpal S.; Hillhouse, Edward W.; Spiess, Joachim

doi:10.1523/jneurosci.23-02-00700.2003

Cited by 173 publications

(136 citation statements)

References 58 publications

(50 reference statements)

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“…Typically, CRH receptors are coupled to G-proteins (G S ) and activate adenylate cyclase (Bale and Vale, 2004), although coupling to additional G-proteins and second messenger cascades has been reported (Grammatopoulos et al, 2001;Dautzenberg and Hauger, 2002;Blank et al, 2003). In the hippocampus, CRH inhibits a calciumactivated potassium current [I K(Ca) ] (Aldenhoff et al, 1983), whereas in the amygdala CRH activates a calcium current (I Ca ) and inhibits I K(Ca) (Rainnie et al, 1992;Yu and Shinnick-Gallagher, 1998).…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-Releasing Hormone Directly Activates Noradrenergic Neurons of the Locus Ceruleus RecordedIn Vitro

Jedema¹,

Grace²

2004

J. Neurosci.

152

124

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The neuropeptide corticotropin-releasing hormone (CRH) activates locus ceruleus (LC) neurons, thereby increasing norepinephrine levels throughout the CNS. Despite anatomical and physiological evidence for CRH innervation of the LC, the mechanism of CRH-evoked activation of LC neurons is unknown. Moreover, given the apparent absence of mRNA for CRH receptors in LC neurons, the exact location of action of CRH within the cerulear region is debated. Using in vitro intracellular recordings from rat brainstem, we examined whether CRH exerts a direct effect on LC neurons and which ionic currents are likely affected by CRH. We demonstrate that CRH dose-dependently increases the firing rate of LC neurons through a direct (TTX-and cadmium-insensitive) mechanism by decreasing a potassium conductance. The CRH-evoked activation of LC neurons is, at least in part, mediated by CRH 1 receptors and a cAMP-dependent second messenger system. These data provide additional support that CRH functions as an excitatory neurotransmitter in the LC and the hypothesis that dysfunction of the CRH peptidergic and noradrenergic systems observed in patients with mood and anxiety disorders are functionally related.

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Section: Introductionmentioning

confidence: 99%

Corticotropin-Releasing Hormone Directly Activates Noradrenergic Neurons of the Locus Ceruleus RecordedIn Vitro

Jedema¹,

Grace²

2004

J. Neurosci.

152

124

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“…However, in vivo studies in rats suggest that AST may be somewhat less potent in preventing some CRHand stress-induced and anxiety-related behaviors (Spina et al, 2000). Thus, potentially lesser potency in combination with strain differences in the regulation of CRH (Blank et al, 2003) may have been in factor in our failure to observe significant effects of AST on wakefulness or sleep in C57BL/6J mice. However, in rats ICV administration of AST and αHelCRH reduced wakefulness and increased NREM only when administered in the dark period (Chang and Opp, 1998).…”

Section: Discussionmentioning

confidence: 95%

“…Strain differences in the CRH system between C57BL/6J mice and BALB/cJ mice have been demonstrated (Blank et al, 2003), but have not been fully elucidated. More work has been conducted on two related strains, C57BL/6ByJ and BALB/cByJ, that are also less and more reactive to stressors, and compared to C57BL/6ByJ mice, BALB/cByJ mice show greater stressor-provoked HPA responses including CRH, adrenocorticotropin hormone and corticosterone (Reviewed in Anisman et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Mouse strains, including C57BL/6J mice, BALB/cJ mice, exhibit differences in undisturbed baseline sleep (Tang and Sanford, 2002). C57BL/6J mice and BALB/cJ mice also differ in the regulation of CRH as is evident by strain differences in signal transduction pathways mediating signal processing of CRH in the hippocampus and in the effects of ICV CRH on contextual fear (Blank et al, 2003). To our knowledge, the potential role of CRH in mediating EEG-determined arousal and sleep in mice has not been examined.…”

Section: Introductionmentioning

confidence: 99%

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Mouse strain differences in the effects of corticotropin releasing hormone (CRH) on sleep and wakefulness

et al. 2008

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Corticotropin releasing hormone (CRH) plays a major role in central nervous system responses to stressors and has been implicated in stress-induced alterations in sleep. In the absence of stressors, CRH contributes to the regulation of spontaneous waking. We examined the effects of CRH and astressin (AST), a non-specific CRH antagonist, on wakefulness and sleep in two mouse strains with differential responsiveness to stress to determine whether CRH might also differentially affect undisturbed sleep and activity. Less reactive C57BL/6J (n=7) and high reactive BALB/cJ (n=7) male mice were implanted with a transmitter for determining sleep via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery and habituation to handling, ICV microinjections of CRH (0.04, 0.2, and 0.4 μg), AST (0.1, 0.4, and 1.0 μg) or vehicle alone (pyrogenfree saline, 0.2 μl) were administered during the fourth h after lights on and sleep was recorded for the subsequent 8 h. Comparisons of wakefulness and sleep were conducted across conditions and across strains. In C57BL/6J mice, REM was significantly decreased after microinjections of CRH (0.2 μg) and CRH (0.4 μg), and NREM and total sleep were decreased after microinjections of CRH (0.4 μg ). CRH (0.4 μg) and AST did not significantly change wakefulness or sleep. In BALB/cJ mice, CRH (0.4 μg) increased wakefulness and decreased NREM, REM and total sleep. AST decreased active wakefulness and significantly increased REM at the low and high dosages. These findings demonstrate that CRH produces changes in arousal when given to otherwise undisturbed mice. Strain differences in the effects of CRH and AST may be linked to the relative responsiveness of C57BL/6J and BALB/cJ mice to stressors and to underlying differences in the CRH system.

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“…in the hippocampus 5,[9][10][11] . Furthermore, it has been shown that in human epidermoid cells, CRH induces the activity as well as the translocation of PKC isoenzymes 12 .…”

mentioning

confidence: 99%

Roles of Protein Kinase A (PKA) and PKC on Corticotropin-Releasing Hormone (CRH)-Induced Elevation of Cytosolic Calcium from Extra- and Intra-cellular Sources

Dermitzaki¹,

Tsatsanis²,

Alexaki³

et al. 2004

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Corticotropin-releasing hormone (CRH) affects cytosolic calcium ion levels. The aim of the present work was to examine the role of protein kinase A (PKA)-and PKC-dependent signalling pathways in mediating the effect of CRH on calcium ion influx (from extra-cellular sources) and calcium ion mobilization (from intra-cellular stores). In this study, we employed a well-known model of neural crest-derived cells, the PC12 rat pheochromocytoma cell line. We found that CRH increased the concentration of cytosolic calcium ions in calcium-rich and in calcium-free media. In both conditions, an inhibitor of PKA phosphorylation abolished the effect of CRH. In contrast, the inhibitor of PKC phosphorylation blocked the effect of CRH only in calcium-free conditions. The phorbol ester PMA, activator of PKC, accelerated the steep of the curve of cytosolic calcium ion increase from intracellular stores. These data suggest that: (a) CRH induces calcium ion entrance into the cytoplasm from both extra-cellular sources (influx) and from intra-cellular stores (mobilization); (b) the PKAdependent signalling pathway mediates both effects of CRH; and (c) the PKC-dependent signalling pathway mediates only the CRH-induced mobilization of calcium ions from intra-cellular stores. Thus, this is the first report demonstrating that distinct signalling pathways control the effects of CRH on calcium ion influx and on calcium ion mobilization from intra-cellular stores. in the hippocampus 5,9-11 . Furthermore, it has been shown that in human epidermoid cells, CRH induces the activity as well as the translocation of PKC isoenzymes 12 . Finally, exposure of neuroblastoma cells to phorbol esters, activators of PKC, results in up-regulation of CRH binding sites suggesting an additional mechanism through which the PKC signalling pathway may modulate some of the biological effects of CRH 13 .Based on the data mentioned above, it has been hypothesized that the effect of CRH on cytosolic calcium ion levels may be mediated by either the PKA or the PKC signalling pathways. It should be noted that a recent report states that this may be true for the skin 14 . Indeed, in corticotroph cells, although PKA mediated the stimulatory effect of dBcAMP and forskolin on calcium ion influx (through voltage-gated Ca ion channels), it only partially mediated the effect of CRH, giving the impression that the effect of CRH on calcium ion influx may be also mediated by a cAMP-independent mechanism 5,15 . Thus, it has been proposed that CRH stimulates calcium ion influx, mainly via L-type Ca ion channels. The observed calcium ion influx, which is independent of action potentials (membrane depolarization) and mediated by PKC, may involve P-type calcium ion channels 16 .The aim of the present work was to elucidate the role of the PKA and PKC signalling pathways in the mediation of the stimulatory effect of CRH on cytosolic ion levels from extra-cellular and intra-cellular calcium ion sources. In this study, we employed a wellknown model of neural crest-derived cells, th...

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Corticotropin-Releasing Factor Receptors Couple to Multiple G-Proteins to Activate Diverse Intracellular Signaling Pathways in Mouse Hippocampus: Role in Neuronal Excitability and Associative Learning

Cited by 173 publications

References 58 publications

Corticotropin-Releasing Hormone Directly Activates Noradrenergic Neurons of the Locus Ceruleus RecordedIn Vitro

Corticotropin-Releasing Hormone Directly Activates Noradrenergic Neurons of the Locus Ceruleus RecordedIn Vitro

Mouse strain differences in the effects of corticotropin releasing hormone (CRH) on sleep and wakefulness

Roles of Protein Kinase A (PKA) and PKC on Corticotropin-Releasing Hormone (CRH)-Induced Elevation of Cytosolic Calcium from Extra- and Intra-cellular Sources

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