Corticotropin-releasing hormone excites adrenocorticotropin-secreting human pituitary adenoma cells by activating a nonselective cation current.

Takano, Koji; Yasufuku‐Takano, Junko; Teramoto, Akira; Fujita, Toshiro

doi:10.1172/jci119008

Cited by 22 publications

(15 citation statements)

References 27 publications

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“…Therefore, it is tempting to speculate that a depolarization-induced rise in intracellular calcium is another positive regulator of CRH gene expression as well as secretion (Tsagarakis et al 1991, Guardiola-Diaz et al 1994. When treated with high extracellular potassium, BE(2)C cells depolarized at above the threshold of the excitation of the voltage-gated calcium channels, which increased the intracellular calcium concentration by increasing the calcium influx through the channels, as previously reported (Yamashita & Hagiwara 1990, Takano et al 1996. In this condition, a significant increase in the transcriptional activation of the CRH gene was observed, supporting the previous work by Seasholtz (Guardiola-Diaz et al 1994).…”

Section: Discussionsupporting

confidence: 89%

Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells

Yamamori¹,

Asai²,

Yoshida³

et al. 2004

Journal of Molecular Endocrinology

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Although corticotropin-releasing hormone (CRH) plays a pivotal role in the regulation of the hypothalamo-pituitary-adrenal axis, the mechanism of CRH gene expression in the neuronal cell is not completely understood. In this study, we examined the transcriptional regulation of human CRH gene 58-promoter, using a human BE(2)C neuroblastoma cell line expressing intrinsic CRH. In particular, we focused on the involvement of calmodulin kinases (CaMKs), which are known to play an important role in excitation-induced gene expression through the rise in intracellular calcium in the central nervous system. RT-PCR analysis confirmed the expression of CaMK as well as CRH mRNA in BE(2)C cells. When we introduced <1·1 kb of the 58-promoter region of the human CRH fused with luciferase reporter gene into the cells, a substantial transcriptional activity was observed, and this was further increased by the activation of the cAMP/PKA pathway. We then examined the effect of activation of CaMKs by introducing the expression vectors of each kinase, revealing a potent stimulatory effect of CaMKIV, but no effect of CaMKII. Depolarization of the cells caused an increase in CRH promoter activity, which was completely abolished by the treatment with the CaMK antagonist K252a. Interestingly, KCREB, a dominant negative form of CREB, antagonized the effect of the CaMKIV-mediated effect. Altogether, we conclude that not only the cAMP/PKA but also the calcium/CaMKIV signaling pathway is involved in the regulation of CRH gene expression. Furthermore, CREB is thought to be involved in CaMK-as well as cAMP/PKA-mediated CRH gene expression. Since the CRH gene is expressed in the neuronal cells of the hypothalamus, the calcium/CaMKIV signaling pathway may play an important role in the excitation-mediated regulation of CRH synthesis.

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Section: Discussionsupporting

confidence: 89%

Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells

Yamamori¹,

Asai²,

Yoshida³

et al. 2004

Journal of Molecular Endocrinology

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“…CRH and AVP have been reported to activate non‐selective cation channels (Takano et al . ; Mani et al . ) in corticotrophs or other cells and a non‐selective Na + ‐dependent conductance is critical for determining the resting membrane potential (Liang et al .…”

Section: Resultsmentioning

confidence: 99%

Large conductance Ca²⁺‐activated K⁺ (BK) channels promote secretagogue‐induced transition from spiking to bursting in murine anterior pituitary corticotrophs

Duncan

Şengül

Tabak

et al. 2015

The Journal of Physiology

105

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Key points Corticotroph cells of the anterior pituitary are electrically excitable and are an integral component of the hypothalamic‐pituitary‐adrenal axis which governs the neuroendocrine response to stress.Corticotrophs display predominantly single spike activity under basal conditions that transition to complex bursting behaviours upon stimulation by the hypothalamic secretagogues corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP); however, the underlying mechanisms controlling bursting are unknown.In this study, we show that CRH and AVP induce different patterns of corticotroph electrical activity, and we use an electrophysiological approach combined with mathematical modelling to show the ionic mechanisms for these differential effects.The data reveal that secretagogue‐induced bursting is dependent on large conductance Ca2+‐activated K+ (BK) channels and is driven primarily by CRH whereas AVP promotes an increase in single‐spike frequency through BK‐independent pathways involving activation of non‐selective cation conductances.As corticotroph excitability is differentially regulated by CRH and AVP this may allow corticotrophs to respond appropriately to different stressors. AbstractAnterior pituitary corticotroph cells are a central component of the hypothalamic‐pituitary‐adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophic hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modelling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium‐ and voltage‐activated potassium (BK) channels in spontaneous and secretagogue‐induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non‐selective conductances. Co‐stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors.

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“…The signaling process responsible for the cAMP-independent component of the CRH response is not known. In a corticotroph, cAMP signaling is proposed to open the VDCCs, probably through activation of nonselective cation channels and subsequent membrane depolarization, with resultant Ca 2ϩ entry that triggers ACTH secretion (357,530). The direct targets of PKA in this process are not known, however.…”

Section: B Pituitary Cellsmentioning

confidence: 99%

PKA-Dependent and PKA-Independent Pathways for cAMP-Regulated Exocytosis

Seino¹,

Shibasaki²

2005

Physiological Reviews

512

447

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Stimulus-secretion coupling is an essential process in secretory cells in which regulated exocytosis occurs, including neuronal, neuroendocrine, endocrine, and exocrine cells. While an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) is the principal signal, other intracellular signals also are important in regulated exocytosis. In particular, the cAMP signaling system is well known to regulate and modulate exocytosis in a variety of secretory cells. Until recently, it was generally thought that the effects of cAMP in regulated exocytosis are mediated by activation of cAMP-dependent protein kinase (PKA), a major cAMP target, followed by phosphorylation of the relevant proteins. Although the involvement of PKA-independent mechanisms has been suggested in cAMP-regulated exocytosis by pharmacological approaches, the molecular mechanisms are unknown. Newly discovered cAMP-GEF/Epac, which belongs to the cAMP-binding protein family, exhibits guanine nucleotide exchange factor activities and exerts diverse effects on cellular functions including hormone/transmitter secretion, cell adhesion, and intracellular Ca(2+) mobilization. cAMP-GEF/Epac mediates the PKA-independent effects on cAMP-regulated exocytosis. Thus cAMP regulates and modulates exocytosis by coordinating both PKA-dependent and PKA-independent mechanisms. Localization of cAMP within intracellular compartments (cAMP compartmentation or compartmentalization) may be a key mechanism underlying the distinct effects of cAMP in different domains of the cell.

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Corticotropin-releasing hormone excites adrenocorticotropin-secreting human pituitary adenoma cells by activating a nonselective cation current.

Abstract: The mechanisms of corticotropin-releasing hormone (CRH)-induced excitation of ACTH-secreting adenoma cells were investigated using the perforated whole-cell

Cited by 22 publications

References 27 publications

Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells

Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells

Large conductance Ca²⁺‐activated K⁺ (BK) channels promote secretagogue‐induced transition from spiking to bursting in murine anterior pituitary corticotrophs

PKA-Dependent and PKA-Independent Pathways for cAMP-Regulated Exocytosis

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Corticotropin-releasing hormone excites adrenocorticotropin-secreting human pituitary adenoma cells by activating a nonselective cation current.

Abstract: The mechanisms of corticotropin-releasing hormone (CRH)-induced excitation of ACTH-secreting adenoma cells were investigated using the perforated whole-cell

Cited by 22 publications

References 27 publications

Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells

Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells

Large conductance Ca2+‐activated K+ (BK) channels promote secretagogue‐induced transition from spiking to bursting in murine anterior pituitary corticotrophs

PKA-Dependent and PKA-Independent Pathways for cAMP-Regulated Exocytosis

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Large conductance Ca²⁺‐activated K⁺ (BK) channels promote secretagogue‐induced transition from spiking to bursting in murine anterior pituitary corticotrophs