Ca2+-mediated activation of ERK in hepatocytes by norepinephrine and prostaglandin F2α: role of calmodulin and src kinases

Melien, Øyvind; Nilssen, Laila Sortvik; Dajani, Olav; Sand, Kristin L.; Iversen, Jens-Gustav; Sandnes, Dagny; Christoffersen, Thoralf

doi:10.1186/1471-2121-3-5

Cited by 29 publications

(7 citation statements)

References 83 publications

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“…In this study, calcium was required for the association between calmodulin and KSR1, and calcium chelation substantially reduced EGF-induced ERK activation in KSR1-expressing cells ( 44 ). This is consistent with prior observations that pretreating hepatocytes with calcium chelators or calmodulin inhibitors, including W-7, markedly reduces ERK activation ( 45 ). In PDAC cells, little is known regarding the role of calmodulin and ERK activation, though early evidence supports a role for calmodulin in enhancing ERK activation in PANC-1 cells, in part via cross-talk with SRC kinase ( 46 ).…”

Section: Discussionsupporting

confidence: 93%

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer

Principe

Aissa

Kumar

et al. 2022

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

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Significance Pancreatic cancer is a leading cause of cancer-related death, in part due to incomplete responses to standard-of-care chemotherapy. In this study, using a combination of single-cell RNA sequencing and high-throughput proteomics, we identified the calcium-responsive protein calmodulin as a key mediator of resistance to the first-line chemotherapy agent gemcitabine. Inhibition of calmodulin led to the loss of gemcitabine resistance in vitro, which was recapitulated using a calcium chelator or Food and Drug Administration–approved calcium channel blockers (CCBs), including amlodipine. In animal studies, amlodipine markedly enhanced therapeutic responses to gemcitabine chemotherapy, reducing the incidence of distant metastases and extending survival. Hence, incorporating CCBs may provide a safe and effective means of improving responses to gemcitabine-based chemotherapy in pancreatic cancer patients.

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Section: Discussionsupporting

confidence: 93%

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer

Principe

Aissa

Kumar

et al. 2022

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

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“…In that regard, we have previously shown that CaM is critical for the 5-HT 1A receptor to activate ERK, in a process involving agonist-induced receptor internalization (30). Similarly, Melien et al (55) showed that ERK activation induced by norepinephrine and prostaglandin F2␣ was sensitive to pharmacological inhibitors of CaM in hepatocytes. Likewise, CaM has been shown to mediate activation of ERK by the -opioid receptor through a pathway involving the transactivation of the epidermal growth factor (EGF) receptor (56).…”

Section: Discussionmentioning

confidence: 78%

Calmodulin Interacts with the Third Intracellular Loop of the Serotonin 5-Hydroxytryptamine1A Receptor at Two Distinct Sites

Turner

Gelasco

Raymond

2004

Journal of Biological Chemistry

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The 5-HT 1A 1 receptor is arguably the most well characterized of the 5-HT receptor subtypes, having been cloned over a decade ago. It has been implicated in numerous physiological and pathological processes, including thermoregulation (1, 2), sexual behavior (3), memory (4), immune function (5), depression (6, 7), and anxiety (8, 9). As a prototypical G proteincoupled receptor (GPCR), the 5-HT 1A receptor couples to a broad array of second messengers, including adenylyl cyclase (10, 11), phospholipase C (12), PKC (13), K ϩ channels (14 -16), mitogen-activated protein kinases (MAPKs) (17, 18), and Na ϩ /H ϩ exchange (18,19). Virtually all of these cellular effects are averted by pretreatment with pertussis toxin, indicating that 5-HT 1A receptors couple specifically and/or preferentially to G i/o proteins.Although previous studies have thoroughly detailed the coupling of the 5-HT 1A receptor to heterotrimeric G proteins and intracellular second messengers, no studies have investigated the possible role of additional receptor-interacting proteins in 5-HT 1A receptor signaling. Growing evidence suggests that GPCRs can bind a variety of proteins, which can subsequently modify receptor signaling, internalization, and/or interaction with G protein subunits. For example, several GPCRs contain C-terminal PDZ motifs that permit them to interact with multiple intracellular proteins, including the Na ϩ /H ϩ exchanger regulatory factor and post-synaptic density protein . The isoform of 14-3-3 protein has been shown to bind and regulate the surface expression of different ␣ 2 -adrenergic receptor subtypes (21). Other reported GPCR-interacting proteins include endothelial nitric-oxide synthase (22), the small nonheterotrimeric G proteins ARF and RhoA (23), and the tyrosine phosphatases SHP-1 and SHP-2 (24).Calmodulin (CaM) is a ubiquitous intracellular Ca 2ϩ -sensor that plays an important role in several downstream GPCR * This work was supported by grants from the Department of Veterans Affairs (Merit Award to J. R. R.), the National Institutes of Health Grants DK52448 and GM63909 (to J. R. R) and DK59950 and MH64795 (to A. K. G.), a pre-doctoral fellowship from the American Heart Association, Mid-Atlantic Affiliate (Grant 0215195U to J. H. T.), and laboratory endowments jointly supported by the MUSC Division of Nephrology and Dialysis Clinics, Inc. (to J. R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.¶ To whom correspondence should be addressed: Medical University of South Carolina, 96 Jonathan Lucas St., Rm. 829 CSB, P. O. Box 250623, Charleston, SC 29425-2227. Tel.: 843-876-5128; Fax: 843-876-5129; E-mail: raymondj@musc.edu. 1 The abbreviations used are: 5-HT, 5-hydroxytryptamine; 8-OH-DPAT, (Ϯ)-8-hydroxy-2-(di-n-propylamino)tetralin; BAPTA-AM, 1,2-bis(o-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid tetra(acetoxymethyl)ester; BRET, bi...

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“…Band density was determined and quantified for ERK1/2 activation (increase relative to control) and is indicated by bars. Bars represent averages Ϯ SE hepatocytes (27). Hcy and its metabolites are known to interact with molecular targets such as neurotransmitter receptors, channels, or transporters and are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs).…”

Section: Discussionmentioning

confidence: 99%

Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway

Moshal¹,

Sen²,

Tyagi³

et al. 2006

American Journal of Physiology-Cell Physiology

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Homocysteine (Hcy) induces matrix metalloproteinase (MMP)-9 in microvascular endothelial cells (MVECs). We hypothesized that the ERK1/2 signaling pathway is involved in Hcy-mediated MMP-9 expression. In cultured MVECs, Hcy induced activation of ERK, which was blocked by PD-98059 and U0126 (MEK inhibitors). Pretreatment with BAPTA-AM, staurosporine (PKC inhibitor), or Gö6976 (specific inhibitor for Ca(2+)-dependent PKC) abrogated ERK phosphorylation, suggesting the role of Ca(2+) and Ca(2+)-dependent PKC in Hcy-induced ERK activation. ERK phosphorylation was suppressed by pertussis toxin (PTX), suggesting the involvement of G protein-coupled receptors (GPCRs) in initiating signal transduction by Hcy and leading to ERK activation. Pretreatment of MVECs with genistein, BAPTA-AM, or thapsigargin abrogated Hcy-induced ERK activation, suggesting the involvement of the PTK pathway in Hcy-induced ERK activation, which was mediated by intracellular Ca(2+) pool depletion. ERK activation was attenuated by preincubation with N-acetylcysteine (NAC) and SOD, suggesting the role of oxidation in Hcy-induced ERK activation. Pretreatment with an ERK1/2 blocker (PD-98059), staurosporine, folate, or NAC modulated Hcy-induced MMP-9 activation as measured using zymography. Our results provide evidence that Hcy triggers the PTX-sensitive ERK1/2 signaling pathway, which is involved in the regulation of MMP-9 in MVECs.

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Ca2+-mediated activation of ERK in hepatocytes by norepinephrine and prostaglandin F2α: role of calmodulin and src kinases

Cited by 29 publications

References 83 publications

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer

Calmodulin Interacts with the Third Intracellular Loop of the Serotonin 5-Hydroxytryptamine1A Receptor at Two Distinct Sites

Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway

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