Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogen-activated protein kinase activation in primary cardiomyocytes via NPY Y5 receptors

Pellieux, Corinne; Sauthier, Thérèse; Domenighetti, Andrea A.; Marsh, Donald J.; Palmiter, Richard D.; Brunner, Hans R.; Pedrazzini, Thierry

doi:10.1073/pnas.030533197

Cited by 89 publications

(88 citation statements)

References 35 publications

(55 reference statements)

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“…These effects appear to represent a biologic role for NPY in modulation of seizure activity, consistent with the following observations: (a) NPY is found at release sites near the glutamatergic presynaptic terminal in the hippocampus (23), (b) NPY is upregulated after acute seizure activity (6,7), (c) NPY receptor expression is altered during epileptogenesis (21), and (d) mice lacking NPY are unable to terminate limbic seizure activity (10). In the absence of any experimental evidence for developmental compensation in Y5R KO mice (20,24,25), we conclude that the antiepileptic actions of NPYare mediated by a hippocampal Y5 receptor.…”

Section: Discussionsupporting

confidence: 69%

Antiepileptic Actions of Neuropeptide Y in the Mouse Hippocampus Require Y5 Receptors

Baraban

2002

Epilepsia

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Summary:Purpose: Recent evidence suggests an antiepileptic role for neuropeptide Y (NPY) in the central nervous system. The precise receptor subtypes mediating the inhibitory actions of NPY in the hippocampal formation, however, remain unclear. In vitro studies suggest a role for Y2 receptors in modulating excitatory hippocampal synaptic transmission and epileptiform discharge. In vivo studies implicate Y5 receptors. Here we used pharmacologic tools and Y5-receptor knockout mice to examine the role of Y5 receptors in mediating the antiexcitatory and antiepileptic actions of NPY in the hippocampal formation.Methods: Hippocampal slices were obtained from agematched wild-type (WT; 129 s3/svimj) and Y5-receptor knockout (Y5R KO) mice generated on the same background strain. Extracellular or whole-cell voltage-clamp recordings were obtained in area CA3 pyramidale. Evoked population spikes or excitatory postsynaptic currents were monitored during bath application of NPY, NPY 13-36 , or human pancreatic polypeptide (hPP). In some slices, zero-magnesium cerebrospinal fluid (CSF) was used to evoke spontaneous epileptiform discharges.Results: NPY and NPY agonists with preference for either Y2 (NPY 13-36 ) or Y5 (hPP) receptor subtypes caused a significant reduction in population spike and excitatory postsynaptic current (EPSC) amplitudes in slices from WT mice. NPY (and NPY agonists) also suppressed zero-magnesium epileptiform burst discharge in slices from WT mice. In contrast, bath application of NPY, NPY 13-36 , or hPP had no effect in slices from Y5R KO mice.Conclusions: NPY modulates excitatory synaptic transmission and inhibits limbic seizure activity in the mouse hippocampus. The antiepileptic actions of NPY, in the mouse, appear to require activation of hippocampal Y5 receptors. Key Words: EPSC-Hippocampus-Peptide-CA3-Mouse.Neuropeptide Y (NPY) is one of several brain peptides capable of inhibiting epileptiform discharge (1-4). Within the hippocampus, a region long implicated in epileptogenesis, NPY has been shown to inhibit excitatory synaptic transmission at Schaffer collateral-to-CA1 and mossy fiber-to-CA3 synapses (5). Hippocampal NPY content is increased after an acute seizure (6,7), and plastic changes in NPY-receptor subtype expression have been noted in various experimental models of limbic seizure activity (8,9). Furthermore, mice lacking NPY are unable to terminate limbic seizures initiated by the glutamate analogue kainic acid (10). Taken together, these findings have led to the hypothesis that NPY, released from ␥-aminobutyric acid (GABA)ergic interneurons during abnormal electrical discharge, reduces presynaptic glutamate release, resulting in a powerful inhibition of limbic seizure activity. The precise receptor mechanisms responsible for the antiepileptic actions of NPY, however, remain uncertain.In the absence of selective NPY-receptor antagonists, in vitro studies using peptide fragments with receptor subtype "preference" suggest that the antiepileptic actions of NPY are mediated through Y2 recept...

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Section: Discussionsupporting

confidence: 69%

Antiepileptic Actions of Neuropeptide Y in the Mouse Hippocampus Require Y5 Receptors

Baraban

2002

Epilepsia

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“…Cardiomyocytes and nonmyocyte cells were purified as described (23) and plated at a density of 0.1 ϫ 10 6 cells/cm 2 on gelatincoated wells and noncoated wells, respectively. After 24 h in culture, cells were switched to no serum medium, and Ang II was added 24 h later.…”

Section: Methodsmentioning

confidence: 99%

Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension

Murat¹,

Pellieux²,

Brunner

et al. 2000

Journal of Biological Chemistry

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Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca 2؉ /calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.

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“…We obtained neonatal cardiomyocytes as described by Pelliux et al 40 from the heart of 2-day-old Sprague-Dawley rat after digestion with type-2 collagenase (Worthington, Lakewood, NJ, USA). We used a two-round preplating in order to deplete cardiomyocyte culture of nonmyocardial cells.…”

Section: Cell Cultures and Treatmentsmentioning

confidence: 99%

Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes

et al. 2003

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Apoptosis plays a role in cardiomyocyte death in several cardiovascular disorders. Here, we show that primary postnatal cardiomyocytes did not die upon activation of the intrinsic (cytochrome c-dependent) apoptotic pathway. Release of cytochrome c from mitochondria to the cytosol occurred, but did not activate the effector phase of apoptosis. Myocardial cells did not express apoptotic protease-activating factor-1 (Apaf-1), the allosteric activator of caspase-9 acting downstream of cytochrome c release. Forced expression of Apaf-1 restored the competence to complete the cytochrome c-induced apoptotic program and this effect was prevented by overexpression of Bcl-X L . However, cardiomyocytes were able to enter the apoptotic program when it was initiated by activation of death receptors, as observed during serum deprivation and metabolic inhibition. Our results indicate that regulation of Apaf-1 expression may be a new regulatory mechanism developed in postmitotic cells in order to prevent irreversible commitment to die after release of cytochrome c.

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Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogen-activated protein kinase activation in primary cardiomyocytes via NPY Y5 receptors

Cited by 89 publications

References 35 publications

Antiepileptic Actions of Neuropeptide Y in the Mouse Hippocampus Require Y5 Receptors

Antiepileptic Actions of Neuropeptide Y in the Mouse Hippocampus Require Y5 Receptors

Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension

Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes

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