Somatostatin Stimulates BK Ca Channels in Rat Pituitary Tumor Cells through Lipoxygenase Metabolites of Arachidonic Acid

Duerson, Kevin; White, Richard E.; Jiang, F; Schönbrunn, Agnes; Armstrong, David M.

doi:10.1016/0028-3908(96)00131-1

Cited by 66 publications

(53 citation statements)

References 55 publications

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“…Our results suggest that agonist-stimulated phosphorylation of the sst2A receptor preferentially involves GRKs. SRIF inhibition of adenylyl cyclase, as well as regulation of other signaling pathways, is blocked by pertussis toxin, which prevents coupling of sst receptors to G i/o (5)(6)(7)(8)(9)(10)(11)(12). However, pertussis toxin pretreatment did not affect SRIF stimulation of sst2A receptor phosphorylation.…”

Section: Discussionmentioning

confidence: 97%

“…Thus, SRIF inhibition of adenylyl cyclase and Ca 2ϩ channels, as well as SRIF stimulation of K ϩ channels, phospholipase C, serine/threonine and tyrosine phosphatases, arachidonic acid release, and mitogen-activated protein kinases are inhibited by pertussis toxin treatment (5)(6)(7)(8)(9)(10)(11)(12). However, some actions of SRIF, such as stimulation of other tyrosine phosphatases as well as inhibition of Na/H exchange, are pertussis toxin-insensitive (13,14).…”

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confidence: 99%

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Agonist-induced Desensitization, Internalization, and Phosphorylation of the sst2A Somatostatin Receptor

Hipkin

Friedman

Clark

et al. 1997

Journal of Biological Chemistry

141

129

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Cellular responsiveness to the inhibitory peptide somatostatin (SRIF) or its clinically used analogs can desensitize with agonist exposure. While desensitization of other seven-transmembrane domain receptors is mediated by receptor phosphorylation and/or internalization, the mechanisms mediating SRIF receptor (sst) desensitization are unknown. Therefore, we investigated the susceptibility of the sst2A receptor isotype to ligandinduced desensitization, internalization, and phosphorylation in GH-R2 cells, a clone of pituitary tumor cells overexpressing this receptor. A 30-min exposure of cells to either SRIF or the analog SMS 201-995 (SMS) reduced both the potency and efficacy of agonist inhibition of adenylyl cyclase. Internalization of receptor-bound ligand was rapid (t1 ⁄2 ‫؍‬ 4 min) and temperature-dependent. SRIF and SMS increased the phosphorylation of the 71-kDa sst2A protein 25-fold within 15 min. Receptor phosphorylation was dependent on both the concentration and time of agonist exposure and was not affected by pertussis toxin pretreatment, indicating that receptor occupancy rather than second messenger formation was required. Receptor phosphorylation was also stimulated by phorbol 12-myristate 13-acetate activation of protein kinase C. Both ligand-stimulated and phorbol 12-myristate 13-acetate-stimulated receptor phosphorylation occurred primarily on serine. These studies are the first demonstration of agonist-dependent desensitization, internalization, and phosphorylation of the sst2A receptor and suggest that phosphorylation may mediate the homologous and heterologous regulation of this receptor.The somatostatin peptides 1 influence endocrine, exocrine, and neuronal function through binding to a family of six G protein-coupled receptors (sst1, sst2A, sst2B, sst3, sst4, and sst5) (1, 2). Within the SRIF receptor family, sst2A receptor mRNA has been detected in many tissues including the brain, pituitary, pancreas, spleen, small intestine, and stomach (1, 2), and the receptor protein has recently been shown to be widely distributed in the mammalian brain (3). Thus, this receptor isotype mediates many of the central and peripheral actions of SRIF.Early studies on the signal transduction mechanisms activated by SRIF showed that sst receptors elicited their actions predominantly via pertussis toxin-sensitive G proteins (1, 2, 4). Thus, SRIF inhibition of adenylyl cyclase and Ca 2ϩ channels, as well as SRIF stimulation of K ϩ channels, phospholipase C, serine/threonine and tyrosine phosphatases, arachidonic acid release, and mitogen-activated protein kinases are inhibited by pertussis toxin treatment (5-12). However, some actions of SRIF, such as stimulation of other tyrosine phosphatases as well as inhibition of Na/H exchange, are pertussis toxin-insensitive (13,14). The network of signaling pathways activated by individual sst receptor isotypes is largely unknown. Signaling mechanisms have been especially difficult to elucidate in the native environment of the receptors because most SRIF target cells exp...

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Agonist-induced Desensitization, Internalization, and Phosphorylation of the sst2A Somatostatin Receptor

Hipkin

Friedman

Clark

et al. 1997

Journal of Biological Chemistry

141

129

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“…In rat hippocampal pyramidal neurons, for instance, SRIF stimulates both AA release and a 5-lipoxygenase metabolite of AA (Schweitzer et al 1993). In GH 4 C 1 cells, lipoxygenase metabolites of AA are second messengers linking SRIF-activated pertussis toxin-sensitive G proteins to pro- tein phosphatases regulating Ca 2+ -activated K + channel activity (White et al 1991;Duerson et al 1996). In transfected CHO-K1 cells, distinct SRIF receptors are functionally coupled to the stimulation of AA release (Bito et al 1994;Alderton et al 2001), and, of them, sst 2 receptors are likely to activate AA release possibly without an involvement of PKA (Alderton et al 2001).…”

Section: Involvement Of Camp-dependent Pathwaysmentioning

confidence: 97%

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Cervia

Fiorini

Pavan

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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The somatotropin release-inhibiting factor somatostatin-14 (SRIF) is known to activate distinct receptor subtypes (sst1-5). In rat pituitary tumor cells (GC cells), sst2 but not sst1 receptors mediate the SRIF-induced inhibition of intracellular concentration of Ca2+ ([Ca2+]i) and are negatively coupled to cAMP-dependent pathways. In the present study, transduction mechanisms coupling distinct SRIF receptors to their specific functional role were investigated with the use of both SRIF agonists with well-known affinity at individual SRIF receptors and the sst2 receptor antagonist L-Tyr(8) isomer of Cyanamid 154806 (CYN-154806). Our results demonstrate that sst1 and sst2 receptors are coupled to distinct signaling pathways in GC cells. In particular, sst2 receptors are negatively coupled to the cAMP-dependent pathway and this pathway is partially responsible for the sst2 receptor-mediated inhibition of [Ca2+]i. In addition, sst1 and sst2 receptors are both coupled to a decrease of arachidonic acid (AA) release with an efficacy similar to that of SRIF, suggesting that SRIF reduces AA release through either a partial activation of both receptors or the activation of one at a time. This finding is important given the well-accepted role for phospholipase A2 (PLA2) as a positive signaling component in transduction pathways of SRIF receptors. sst1 and sst2 receptor negative coupling to PLA2/AA pathways does not seem to be implicated in the SRIF-induced inhibition of [Ca2+]i. The possible role for the SRIF-mediated inhibition of AA release in GC cell function remains to be elucidated.

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“…A A has been shown to activate a large conductance (160 pS) K ϩ channel directly in cardiac atrial muscle (Kim and Clapham, 1989) and a small conductance (23 pS) K ϩ channel in smooth muscle (for review, see Ordway et al, 1991). The lipoxygenase metabolites of A A also activate the cardiac, muscarinic-activated K ϩ channel, stimulate BK Ca channels in rat pituitary tumor cells (Duerson et al, 1996), and modulate S-type K ϩ channels in Aplysia (Piomelli et al, 1987). In central neurons, A A either depresses or enhances K ϩ currents through lipoxygenase or cyclooxygenase metabolites (Keyser and Alger, 1990;Schweitzer et al, 1990;Zona et al, 1993).…”

Section: Abstract: Arachidonate; Potassium Currents; Stratum Oriens mentioning

confidence: 99%

Arachidonic Acid Inhibits Transient Potassium Currents and Broadens Action Potentials during Electrographic Seizures in Hippocampal Pyramidal and Inhibitory Interneurons

Keros

McBain

1997

J. Neurosci.

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The transient outward potassium current was studied in outside-out macropatches excised from the soma of CA1 pyramidal neurons and stratum (st.) oriens-alveus inhibitory interneurons in rat hippocampal slices. Arachidonic acid dose dependently decreased the charge transfer associated with the transient current, concomitant with an increase in the rate of current inactivation. Arachidonic acid (A A) did not affect the voltage dependence of steady state inactivation but did prolong the period required for complete recovery from inactivation. The effects of A A were mimicked by the nonmetabolizable analog of A A, 5,8,11,14-eicosatetraynoic acid, suggesting that metabolic products of A A were not responsible for the observed blocking action. In addition, A A blocked st. oriensalveus-lacunosum-moleculare interneuron transient currents but not currents recorded from basket cell interneurons. In current clamp experiments, A A was without effect on the action potential waveform of CA1 pyramidal neurons under control recording conditions. In voltage-clamp experiments, the use of a test pulse paradigm, designed to mimic the action potential voltage trajectory, revealed that the transient current normally associated with a single spike deactivates too rapidly for A A to have an effect. Transient currents activated by longer duration "action potential" waveforms, however, were attenuated by A A. Consistent with this finding was the observation that A A broadened interictal spikes recorded in the elevated [K ϩ ] o model of epilepsy. These data suggest that A A liberated from hippocampal neurons may act to block the transient current selectively in both CA1 pyramidal neurons and inhibitory interneurons and to broaden action potentials selectively under pathological conditions.

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Somatostatin Stimulates BK Ca Channels in Rat Pituitary Tumor Cells through Lipoxygenase Metabolites of Arachidonic Acid

Cited by 66 publications

References 55 publications

Agonist-induced Desensitization, Internalization, and Phosphorylation of the sst2A Somatostatin Receptor

Agonist-induced Desensitization, Internalization, and Phosphorylation of the sst2A Somatostatin Receptor

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Arachidonic Acid Inhibits Transient Potassium Currents and Broadens Action Potentials during Electrographic Seizures in Hippocampal Pyramidal and Inhibitory Interneurons

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