Neuropeptide Y (NPY) exerts a variety of effects including increased blood pressure and food intake and decreased anxiety. The increase in blood pressure occurs in conjunction with co- existing transmitters such as ATP and norepinephrine. The long- term objective of research in this laboratory is to reveal the mechanism(s) by which neuropeptides produce physiological changes. Bovine chromaffin cells provide a useful model with which to study neuropeptide action since these cells synthesize and secrete NPY in response to stimulation with nicotine. The goal of the current proposal is to gain insight into the physiological role of NPY as a co-transmitter with ATP. NPY binds to chromaffin cell receptors of the Y1 subtype and inhibits forskolin stimulated adenylate cyclase activity. Our preliminary data show that it does not alter chromaffin cell intracellular Ca2+ concentration ([Ca2+]i) or inositol phosphate formation unless ATP is added to culture media along with NPY. NPY can significantly enhance both the ATP stimulated increase in inositol phosphate formation and [Ca2+]i. The chromaffin cell response to this action is unknown but may include the regulation of neurotransmitter synthesis since increased inositol phosphate formation and [Ca2+]i could have been shown to result in increased tyrosine hydroxylase synthesis. In addition, an increase in [Ca2+]i could stimulate tyrosine hydroxylase activity acutely due to increased enzyme phosphorylation mediated by CaM kinase II. Our hypothesis is that NPY and ATP are co- transmitters in chormaffin cells that serve to increase [Ca2+]i by increasing inositol phosphate formation with the resultant effect of increased catecholamine biosynthesis.
The specific aims are to characterize the enhancing effect of NPY on ATP- stimulated inositol phosphate formation, identify the ATP receptor subtype mediating the stimulation of InsP formation and increased [Ca2+]i, determine the specificity of the ATP potentiating effect of NPY and discover the response of the chromaffin cell to increased intracellular Ca2+. These studies will further our understanding of the physiological role of neuropeptides and their involvement in co-transmission. Information will be provided which may lead to improved therapy of diseases particularly involving aberrations in transmission by catecholamines e.g., epilepsy, anorexia, alcoholism, and hypertension.
| Li, Xinying; Ikezu, Tsuneya; Hexum, Terry D (2004) Betagamma subunits mediate the NPY enhancement of ATP-stimulated inositol phosphate formation. Peptides 25:267-74 |
| Drakulich, Desinee A; Spellmon, Calvin; Hexum, Terry D (2004) Effect of the ecto-ATPase inhibitor, ARL 67156, on the bovine chromaffin cell response to ATP. Eur J Pharmacol 485:137-40 |
| Drakulich, D A; Walls, A M; Toews, M L et al. (2003) Neuropeptide Y receptor-mediated sensitization of ATP-stimulated inositol phosphate formation. J Pharmacol Exp Ther 307:559-65 |
