Enhanced activation of Akt and extracellular‐regulated kinase pathways by simultaneous occupancy of Gq‐coupled 5‐HT2A receptors and Gs‐coupled 5‐HT7A receptors in PC12 cells

Johnson-Farley, Nadine; Kertesy, Sylvia B.; Dubyak, George R.; Cowen, David L.

doi:10.1111/j.1471-4159.2004.02832.x

Cited by 52 publications

(51 citation statements)

References 39 publications

(82 reference statements)

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“…The low levels of ERK1/2 phosphorylation may explain why other studies found no effect of this Epac-selective cAMP analog on ERK1/2 activity in PC12 cells (Enserink et al, 2002;JohnsonFarley et al, 2005). In agreement with a role of Epac in cAMP-induced ERK1/2 activation in PC12 cells, overexpression of Epac1 enhances ERK1/2 activation upon stimulation of G s -coupled 5-HT 7A receptors in these cells (Johnson-Farley et al, 2005).…”

Section: )supporting

confidence: 54%

Epac Activation Converts cAMP from a Proliferative into a Differentiation Signal in PC12 Cells

Kiermayer

Biondi

Imig

et al. 2005

MBoC

105

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Elevation of the intracellular cAMP concentration ([cAMP]i ) regulates metabolism, cell proliferation, and differentiation and plays roles in memory formation and neoplastic growth. cAMP mediates its effects mainly through activation of protein kinase A (PKA) as well as Epac1 and Epac2, exchange factors activating the small GTPases Rap1 and Rap2. However, how cAMP utilizes these effectors to induce distinct biological responses is unknown. We here studied the specific roles of PKA and Epac in neuroendocrine PC12 cells. In these cells, elevation of [cAMP] i activates extracellular signal-regulated kinase (ERK) 1/2 and induces low-degree neurite outgrowth. The present study showed that specific stimulation of PKA triggered ERK1/2 activation that was considerably more transient than that observed upon simultaneous activation of both PKA and Epac. Unexpectedly, the PKA-specific cAMP analog induced cell proliferation rather than neurite outgrowth. The proliferative signaling pathway activated by the PKA-specific cAMP analog involved activation of the epidermal growth factor receptor and ERK1/2. Activation of Epac appeared to extend the duration of PKA-dependent ERK1/2 activation and converted cAMP from a proliferative into an anti-proliferative, neurite outgrowthpromoting signal. Thus, the present study showed that the outcome of cAMP signaling can depend heavily on the set of cAMP effectors activated. INTRODUCTIONThe normal development of organisms requires a tight coordination between growth and differentiation. Importantly, the regulation of this decision is altered in disease states, most notably in cancer, where growth signals overcome the physiological processes of differentiation. The differentiation of neuronal cells is important for the regular function of the brain. Thus, there is interest in understanding the molecular signaling mechanisms that regulate cell proliferation and differentiation.In a number of cells, most notably of neuronal origin, G s protein-coupled receptors (GsPCR) are key regulators of cell proliferation, differentiation, and survival and play important roles in numerous biological processes such as neoplasia, learning, and memory formation (Kandel, 2001;Spada and Lania, 2002;Wang et al., 2004). The signaling cascades downstream of GsPCRs to regulate these events include activation of adenylyl cyclase, elevation of the intracellular cAMP concentration ([cAMP] i ), and modulation of the extracellular signal-regulated kinase (ERK) 1/2 pathway (Stork, 2003).cAMP binds to and directly activates protein kinase A (PKA) as well as the cAMP binding guanine nucleotide exchange factors Epac1 and -2, which in turn stimulate the small GTPases Rap1 and Rap2. Together, PKA and Epacs appear to mediate the majority of effects of cAMP in mammalian cells (de Rooij et al., 1998;Kawasaki et al., 1998;Bos, 2003). Nevertheless, most work on cAMP-dependent pathways has been centered on the role of PKA. For instance, a role of PKA in memory formation has been verified in numerous in vitro and in vivo studies t...

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Section: )supporting

confidence: 54%

Epac Activation Converts cAMP from a Proliferative into a Differentiation Signal in PC12 Cells

Kiermayer

Biondi

Imig

et al. 2005

MBoC

105

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“…The PKA inhibitor, H89, did not have an effect on GLP-1 protective action due, probably, to a different system (ex vivo culture), that used a culture medium with several growth factors contained in the fetal calf serum, and the possibility of cAMP induced ERK1/2 activation in a PKA-independent manner. In this sense, the role of cAMP-regulated guanine nucleotide exchange factor (Epac) in GLP-1 receptor-mediated signal transduction in b cells, and Epac-dependent, PKA-independent ERK1/2 activation in response to cAMP has been described (Busca et al 2000, Lin et al 2003, Holz 2004, Johnson-Farley et al 2005, Fang & Olah 2007. On the other hand, treatment with PD98059, which blocks ERK1/2 pathway by inhibiting MAP kinase (MEK), abrogates the effect of GLP-1 on cytokine-treated cultures.…”

Section: Discussionmentioning

confidence: 99%

Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1

Blandino-Rosano¹,

Pérez-Arana²,

Mellado-Gil³

et al. 2008

Journal of Molecular Endocrinology

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Pancreatic b-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of b-cell mass loss by pro-inflammatory cytokineinduced apoptosis, influences of a pro-inflammatory environment on b-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic b cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2 0 -deoxyuridine label respectively, in the presence-absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1b, interferon (IFN)-g, and tumour necrosis factor-a (TNF-a) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in b-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased b-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and b-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic b cells as well as to delay the development of overt diabetes.

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“…Although PKA is a main downstream target of cAMP signaling (Beebe 1994;Nguyen and Woo 2003), PKA-independent activation of ERK and mTOR signaling cascades has been demonstrated. For example, activation of 5-HT7A receptors results in stimulation of cAMP-regulated guanine exchange factors (cAMPGEFs) (Johnson-Farley et al 2005). Thus, direct coupling of cAMP to intracellular signaling pathways, such as ERK, via cAMP-GEFs, may occur downstream of the ␤-AR receptor to enhance the maintenance of LTP.…”

Section: Discussionmentioning

confidence: 99%

β-Adrenergic receptor activation during distinct patterns of stimulation critically modulates the PKA-dependence of LTP in the mouse hippocampus

Gelinas

Tenorio²,

Lemon³

et al. 2008

Learn. Mem.

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Activation of ␤-adrenergic receptors (␤-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to ␤-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms of long-lasting hippocampal LTP. How does ␤-AR activation affect the PKA-dependence, and persistence, of LTP elicited by distinct stimulation frequencies? Here, we use in vitro electrophysiology to show that patterns of stimulation determine the temporal phase of LTP affected by ␤-AR activation. In addition, only specific patterns of stimulation recruit PKA-dependent LTP following ␤-AR activation. Impairments of PKA-dependent LTP maintenance generated by pharmacologic or genetic deficiency of PKA activity are also abolished by concurrent activation of ␤-ARs. Taken together, our data show that, depending on patterns of synaptic stimulation, activation of ␤-ARs can gate the PKA-dependence and persistence of synaptic plasticity. We suggest that this may allow neuromodulatory receptors to fine-tune neural information processing to meet the demands imposed by numerous synaptic activity profiles. This is a form of "metaplasticity" that could control the efficacy of consolidation of hippocampal long-term memories.

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Enhanced activation of Akt and extracellular‐regulated kinase pathways by simultaneous occupancy of G_q‐coupled 5‐HT_2A receptors and G_s‐coupled 5‐HT_7A receptors in PC12 cells

Cited by 52 publications

References 39 publications

Epac Activation Converts cAMP from a Proliferative into a Differentiation Signal in PC12 Cells

Epac Activation Converts cAMP from a Proliferative into a Differentiation Signal in PC12 Cells

Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1

β-Adrenergic receptor activation during distinct patterns of stimulation critically modulates the PKA-dependence of LTP in the mouse hippocampus

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