Interactions of multiple signaling pathways in neuropeptide Y-mediated bimodal vascular smooth muscle cell growth

Abstract

Neuropeptide Y (NPY), a sympathetic cotransmitter, acts via G protein-coupled receptors to stimulate constriction and vascular smooth muscle cell (VSMC) proliferation through interactions with its Y1 receptors. However, VSMC proliferation appears bimodal, with high-and low-affinity peaks differentially blocked by antagonists of both Y1 and Y5 receptors. Here, we sought to determine the signaling mechanisms of NPY-mediated bimodal mitogenesis. In rat aortic VSMCs, NPY's mitogenic effect at all concentrations was blocked by pertussis toxin and was associated with decreased forskolin-stimulated cAMP levels. NPY also increased intracellular calcium levels; in contrast to mitogenesis, this effect was dose dependent. The rise in intracellular Ca 2+ depended on extracellular Ca 2+ and was mediated via activation of Y1 receptors, but not Y5 receptors. Despite differences in calcium, the signaling pathways activated at low and high NPY concentrations were similar. The mitogenic effect of the peptide at all doses was completely blocked by inhibitors of calcium/calmodulin-dependent kinase II (CaMKII), protein kinase C (PKC), and mitogen-activated protein kinase kinase, MEK1/2. Thus, in VSMCs, NPY-mediated

Neuropeptide Y Y5 Receptor Promotes Cell Growth through Extracellular Signal-Regulated Kinase Signaling and Cyclic AMP Inhibition in a Human Breast Cancer Cell Line

“…Further, activation of Y5R increases mitogen-activated protein kinase and protein kinase C activities in a calciumindependent manner in cardiac myocytes (22). In rat aortic vascular smooth muscle cells, activation of Y5R had no effect on intracellular Ca 2+ mobilization but increased cell growth (37). The lack of Ca 2+ mobilization by Y5R in BT-549 cells is consistent with the above findings albeit in different cellular systems.…”

Inhibitory effect of D1-like dopamine receptors on neuropeptide Y-induced proliferation in vascular smooth muscle cells

“…As a major mitogenic factor, NPY has been shown to stimulate the proliferation of VSMCs. 3 Our previous study found that in the presence of the dopamine receptor, the α 1 -adrenergic receptor-mediated VSMC proliferation is reduced. The present study also found D 1 -like receptor agonist reduced the NPY-mediated VSMC proliferation, indicating that the dopamine receptor inhibits the VSMC proliferation induced by NPY.…”

“…4 As a major mitogenic factor, NPY has been shown to stimulate the proliferation of VSMCs. 3 We hypothesize that the activation of the D 1 -like receptor might inhibit the NPY-mediated VSMC proliferation. Therefore, our present study was designed to investigate the possible role of D 1 -like receptors on NPY-mediated VSMC proliferation and examine its potential mechanism(s).…”

Crucial Role for Ca 2+ /Calmodulin-Dependent Protein Kinase-II in Regulating Diastolic Stress of Normal and Failing Hearts via Titin Phosphorylation

“…45 An issue to be addressed in future work is the significant cross-talk that exists between the PKCα and CaMKII pathways. 46 Activation of 1 pathway could well affect the phosphorylation of titin sites predominantly phosphorylated via the cross-talking pathway. In summary, S12022/S12884 is the key CaMKIIδ-phosphosite in the constitutively expressed human/mouse PEVK-domain, which can modulate titin stiffness, but additional CaMKII-sites are present in this region.…”

“…The CaMKII and ERK1/2 pathways interact in several ways (while cross-talking to the PKCα pathway). 46 Furthermore, there is synergy between the CaMKII and PKA pathways, 27,48 and the latter also targets titin-N2Bus. 17,19,20 Altering CaMKII expression/activity is thus likely to have secondary effects on the expression/activity of other PKs, with consequences for N2Bus-phosphorylation.…”