A Bovine Adrenocortical Kv1.4 K+ Channel Whose Expression Is Potently Inhibited by ACTH

Enyeart, Judith A.; Xu, Lin; Enyeart, John J.

doi:10.1074/jbc.m004214200

Cited by 21 publications

(17 citation statements)

References 43 publications

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“…However, corticotropin inhibits bTREK-1 K ϩ channel activity, depolarizes AZF cells, stimulates cortisol secretion, and inhibits the expression of bKv1.4 mRNA at 100-to 1000-fold lower concentrations (Mlinar et al, 1993a;Enyeart et al, 2000). We found that corticotropin also potently induced the expression of bTREK-1 mRNA at picomolar concentrations.…”

Section: Resultsmentioning

confidence: 60%

Corticotropin Induces the Expression of TREK-1 mRNA and K⁺Current in Adrenocortical Cells

Enyeart

Danthi²,

Enyeart³

2003

Mol Pharmacol

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Bovine adrenal zona fasciculata (AZF) cells express a two-pore/ four-transmembrane segment bTREK-1 K ϩ channel that sets the resting potential and couples hormonal signals to depolarizationdependent Ca 2ϩ entry and cortisol secretion. It was discovered that corticotropin (1-2000 pM) enhances the expression of bTREK-1 mRNA and membrane current in cultured AZF cells. Forskolin and 8-pcpt-cAMP mimicked corticotropin induction of bTREK-1 mRNA, but angiotensin II (AII) was ineffective. The induction of bTREK-1 mRNA by corticotropin was partially blocked by the A-kinase antagonist H-89. 8-(4-Chloro-phenylthio)-2-Omethyladenosine-3Ј-5Ј-cyclic monophosphate, a cAMP analog that activates cAMP-regulated guanine nucleotide exchange factors (Epac), failed to increase bTREK-1 mRNA. Corticotropinstimulated increases in bTREK-1 mRNA were eliminated by inhibitors of protein synthesis or gene transcription. bTREK-1 current disappeared after 24 h in serum-supplemented medium, but in the presence of corticotropin, bTREK-1 expression was maintained for at least 48 h. The enhancement of bTREK-1 mRNA and ionic current contrasts with the corticotropin-induced down-regulation of the Kv1.4 voltage-gated K ϩ current and associated mRNA in AZF cells. These results demonstrate that corticotropin rapidly and potently induces the expression of bTREK-1 in AZF cells at the pretranslational level by a cAMP-dependent mechanism that is partially dependent on A-kinase but independent of Epac and Ca 2ϩ . They further indicate that prolonged stimulation of AZF cells by corticotropin, as occurs during long-term stress or disease, may produce pronounced changes in the expression of genes encoding ion channels, thereby reshaping the electrical properties of these cells to enhance or limit cortisol secretion.Although cortisol-secreting cells of the adrenal zona fasciculata (AZF) lack Na ϩ -dependent action potentials, a hallmark of excitable cells, ion channels play a prominent role in the physiology of cortisol secretion (Enyeart et al., , 1996bMlinar et al., 1993a). AZF cells express both voltagegated Ca 2ϩ and K ϩ channels and maintain resting membrane potentials near the K ϩ equilibrium potential (Mlinar et al., 1993a,b;Mlinar and Enyeart, 1993). Corticotropin-and AII-stimulated cortisol secretion by AZF cells involves depolarization-dependent Ca 2ϩ entry through Ca 2ϩ channels Mlinar et al., 1993a,b).Ion channels in adrenal cortical cells have been identified and characterized using a combination of patch clamp and molecular methods. In addition to low voltage-activated Ttype Ca 2ϩ channels, bovine AZF cells express two types of K ϩ -selective channels. These include a voltage-gated, rapidly inactivating Kv1.4 K ϩ channel and a noninactivating, background K ϩ channel (Mlinar et al., 1993a;Mlinar and Enyeart, 1993;Enyeart et al., 2002). Recently, we identified the background channel as bTREK-1 (or KCNK2), a member of the two-pore, four-transmembrane-segment (2P/4TMS) family of K ϩ channels (Fink et al., 1996;Maingret et al., 2000;Goldstein...

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Section: Resultsmentioning

confidence: 60%

Corticotropin Induces the Expression of TREK-1 mRNA and K⁺Current in Adrenocortical Cells

Enyeart

Danthi²,

Enyeart³

2003

Mol Pharmacol

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“…Physiological Significance-The results of this and previous studies strongly suggest that ACTH exerts long term control over the electrical properties of AZF cells by regulating the expression of genes that code for ion channels (10,36,50). Ca v 3.2 Ca 2ϩ channels function as the primary pathway for depolarization-dependent Ca 2ϩ entry, leading to cortisol secretion by these cells (2).…”

Section: Discussionmentioning

confidence: 99%

ACTH Induces Cav3.2 Current and mRNA by cAMP-dependent and cAMP-independent Mechanisms

Liu

Enyeart

2010

Journal of Biological Chemistry

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“…This and other studies demonstrate that adrenocorticotropin and cAMP exert long-term control over the electrical properties of AZF cells by regulating the expression of genes that code for ion channels (Enyeart et al, 2000(Enyeart et al, , 2003. Adrenocorticotropin may function through cAMP-dependent and independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…First, although the hydrolyzable 8-(4-chlorophenylthio)-cAMP analogs and their metabolites at low concentrations all induced bTREK-1 expression, none of these down-regulated the Kv1.4 current whose expression is inhibited by a PKA-dependent mechanism (Enyeart et al, 2000). In contrast, 8-Br-cAMP and 6-Bnz-cAMP, as well as adrenocorticotropin, at concentrations that induced bTREK-1 all inhibited the expression of Kv1.4 current (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Cortisol synthesis is stimulated by the pituitary peptide adrenocorticotropin (Simpson and Waterman, 1988). Adrenocorticotropin exerts rapid and longterm control over the electrical and secretory properties of AZF cells by regulating both the activity of pre-existing ion channels and the expression of genes coding for these same channel proteins Enyeart et al, 1996Enyeart et al, , 2000Enyeart et al, , 2003Liu et al, 2008). In particular, in whole-cell recordings, adrenocorticotropin rapidly (within seconds to minutes) inhibits the activity of bTREK-1 K ϩ channels by a cAMP-dependent mechanism En-yeart et al, 1996En-yeart et al, , 2000En-yeart et al, , 2003.…”

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cAMP Analogs and Their Metabolites Enhance TREK-1 mRNA and K⁺Current Expression in Adrenocortical Cells

Enyeart¹,

Liu²,

Enyeart³

2009

Mol Pharmacol

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bTREK-1 K ϩ channels set the resting membrane potential of bovine adrenal zona fasciculata (AZF) cells and function pivotally in the physiology of cortisol secretion. Adrenocorticotropic hormone controls the function and expression of bTREK-1 channels through signaling mechanisms that may involve cAMP and downstream effectors including protein kinase A (PKA) and exchange protein 2 directly activated by cAMP (Epac2). Using patch-clamp and Northern blot analysis, we explored the regulation of bTREK-1 mRNA and K ϩ current expression by cAMP analogs and several of their putative metabolites in bovine AZF cells. At concentrations sufficient to activate both PKA and Epac2, 8-bromoadenosine-cAMP enhanced the expression of both bTREK-1 mRNA and K ϩ current. N 6 -Benzoyladenosine-cAMP, which activates PKA but not Epac, also enhanced the expression of bTREK-1 mRNA and K ϩ current measured at times from 24 to 96 h. An Epac-selective cAMP analog, 8-(4-chlorophenylthio)-2Ј-O-methyl-cAMP (8CPT-2Ј-OMe-cAMP), potently stimulated bTREK-1 mRNA and K ϩ current expression, whereas the nonhydrolyzable Epac activator 8-(4-chlorophenylthio)-2Ј-O-methyl-cAMP, Sp-isomer was ineffective. Metabolites of 8CPT-2Ј-OMe-cAMP, including 8-(4-chlorophenylthio)-2Ј-O-methyladenosine-5Ј-O-monophosphate and 8CPT-2Ј-OMe-adenosine, promoted the expression of bTREK-1 transcripts and ion current with a temporal pattern, potency, and effectiveness resembling that of the parent compound. Likewise, at low concentrations, 8-(4-chlorophenylthio)-cAMP (8CPT-cAMP; 30 M) but not its nonhydrolyzable analog 8-(4-chlorophenylthio)-cAMP, Sp-isomer, enhanced the expression of bTREK-1 mRNA and current. 8CPT-cAMP metabolites, including 8CPT-adenosine and 8CPT-adenine, also increased bTREK-1 expression. These results indicate that cAMP increases the expression of bTREK-1 mRNA and K ϩ current through a cAMP-dependent but Epac2-independent mechanism. They further demonstrate that one or more metabolites of 8-(4-chlorophenylthio)-cAMP analogs potently stimulate bTREK-1 expression by activation of a novel cAMP-independent mechanism. These findings raise significant questions regarding the specificity of 8-(4-chlorophenylthio)-cAMP analogs as cAMP mimetics.

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A Bovine Adrenocortical Kv1.4 K+ Channel Whose Expression Is Potently Inhibited by ACTH

Cited by 21 publications

References 43 publications

Corticotropin Induces the Expression of TREK-1 mRNA and K⁺Current in Adrenocortical Cells

Corticotropin Induces the Expression of TREK-1 mRNA and K⁺Current in Adrenocortical Cells

ACTH Induces Cav3.2 Current and mRNA by cAMP-dependent and cAMP-independent Mechanisms

cAMP Analogs and Their Metabolites Enhance TREK-1 mRNA and K⁺Current Expression in Adrenocortical Cells

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A Bovine Adrenocortical Kv1.4 K+ Channel Whose Expression Is Potently Inhibited by ACTH

Cited by 21 publications

References 43 publications

Corticotropin Induces the Expression of TREK-1 mRNA and K+Current in Adrenocortical Cells

Corticotropin Induces the Expression of TREK-1 mRNA and K+Current in Adrenocortical Cells

ACTH Induces Cav3.2 Current and mRNA by cAMP-dependent and cAMP-independent Mechanisms

cAMP Analogs and Their Metabolites Enhance TREK-1 mRNA and K+Current Expression in Adrenocortical Cells

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Resources

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Corticotropin Induces the Expression of TREK-1 mRNA and K⁺Current in Adrenocortical Cells

Corticotropin Induces the Expression of TREK-1 mRNA and K⁺Current in Adrenocortical Cells

cAMP Analogs and Their Metabolites Enhance TREK-1 mRNA and K⁺Current Expression in Adrenocortical Cells