application) The objective of this proposal is the characterization of a novel receptor first described as a specific binding site in 1986 by the PI. Radioligand binding studies were the focus of the first five years of this project. I1-imidazoline sites have an unique ligand specificity, although they recognize many adrenergic and histamine H2 ligands. In brain, I1-sites are expressed mainly in the brainstem reticular formation. I1 are localized to plasma membrane and may be coupled to G-proteins, unlike the mitochondrial I2-site. In brainstem, the I1-receptor may mediate the sympatholytic actions of imidazolines. Chromaffin cells of the adrenal medulla and a tumor cell line derived from them (PC 12 pheochromocytoma) express I1-sites in the absence of alpha2-adrenergic receptors as shown by binding, gene expression, and signaling studies. Imidazoline receptors on these cells are coupled to phosphatidylcholine-selective phospholipase C (PC-PLC) leading to the generation of arachidonic acid and its metabolites and to diacylglycerides (DAG). Selective I1-agonists have been developed and are in clinical use in Europe for control of hypertension without severe sedation. Development of more specific imidazoline agonists may provide new avenues for treatment of hypertension, heart failure and even chronic stress. The planned experiments have 3 major aims.
Aim 2 exploits the PC 12 cell model for studies of signaling pathways.
The third aim will apply these findings in vivo.
Aim 1 will determine the contrasts and interactions between I1-imidazoline and alpha2-adrenergic receptors in the brainstem of intact hypertensive rats, in medullary slices, and in cell lines stably transfected with genes encoding both receptors. Contrasts and interactions will be determined for cardiovascular regulation in the medulla oblongata, control of levels of extracellular neurotransmitters as determined by in vivo microdialysis, and release of arachidonic acid.
Aim 2 will focus on the signaling pathways coupled to the I1-imildazoline receptor. The I1,-receptor is unique in that it couples to PC-PLC without generating inositol phosphates, or activating phospholipase D.
Aim 3 will apply the knowledge obtained in the first two aims to the hypertensive rat in vivo. Preliminary results show that microinjection of a PC-PLC inhibitor into the RVLM blocks the antihypertensive action of systemic moxonidine. In summary, we will focus on a novel receptor and its coupling to the recently-recognized PC-PLC signal transduction pathway, and map the steps along the path from receptor activation to the physiologic response at the organismic level.
| Xu, Chuan; Arinze, Ifeanyi J; Johnson, Janean et al. (2008) Metabolic dysregulation in the SHROB rat reflects abnormal expression of transcription factors and enzymes that regulate carbohydrate metabolism. J Nutr Biochem 19:305-12 |
| Ernsberger, Paul; Johnson, Janean L; Rosenthal, Talma et al. (2007) Therapeutic actions of allylmercaptocaptopril and captopril in a rat model of metabolic syndrome. Am J Hypertens 20:866-74 |
| Ernsberger, Paul; Koletsky, Richard J (2007) Metabolic actions of angiotensin receptor antagonists: PPAR-gamma agonist actions or a class effect? Curr Opin Pharmacol 7:140-5 |
| Ishizuka, T; Ernsberger, P; Liu, S et al. (1998) Phenotypic consequences of a nonsense mutation in the leptin receptor gene (fak) in obese spontaneously hypertensive Koletsky rats (SHROB). J Nutr 128:2299-306 |
| Ernsberger, P; Friedman, J E; Koletsky, R J (1997) The I1-imidazoline receptor: from binding site to therapeutic target in cardiovascular disease. J Hypertens Suppl 15:S9-23 |
