The proposed work attempts to define the pathway mediating neuromodulatory effects of natriuretic peptides which produce a variety of hypotensive effects including diuresis, vasodilation, and inhibition of both steroidogenesis and adrenergic neurotransmissions. Past work found natriuretic peptides to inhibit neurotransmission via """"""""clearance"""""""" (ANP C) receptors coupling to a pertussis toxin sensitive process (that does not involve a reduction in cytoplasmic calcium concentrations. It is induced catecholamine release. The hypothesized pathway includes (ANP C) receptors interacting with GTP binding proteins to suppress phospholipase C activity, protein kinase C activity and catecholamine release. Experiments will be performed in a rat pheochromocytoma adrenergic cell line, PC12 cells. The PC12 cells allow monitoring of the complete sequence of proposed events (i.e., receptors, GTP binding proteins, phospholipase C activity, protein kinase C activity, and catecholamine release).
The specific aims i nclude: 1) assessing the contribution of [ANP C receptors to neuromodulatory effects of natriuretic peptides; 2) assessing the contribution of GTP binding proteins to neuromodulatory actions of natriuretic peptides; and 3) assessing the involvement of phospholipase C and protein kinase C in neuromodulatory DA release actions of natriuretic peptides. The first specific aim will examine effects of both ANP C receptor activation and ablation on subsequent events in the proposed pathway. The second specific aim tests for coupling of GTP binding proteins to the ANP C receptor, phospholipase C and subsequent events in the hypothesized pathway. The third specific aim tests whether suppressed phospholipase C and protein kinase C activities are essential for neuromodulatory influences of natriuretic peptides.] These results will impact on the natriuretic peptide field by identifying alternative signal transduction pathways to guanylyl cyclase activation, the pathway currently perceived to mediate all natriuretic peptide actions. The primary contribution will involve a critical assessment of the natriuretic peptide receptor involved in mediating neuromodulatory effects and the coupling of this receptor to GTP binding proteins. The proposed work will test if the (ANP C) receptor specifically mediates neuromodulatory actions of natriuretic peptides.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL042525-04A2
Application #
2220555
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1991-06-01
Project End
1998-06-30
Budget Start
1995-07-20
Budget End
1996-06-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Trachte, George J (2003) Natriuretic peptides suppress protein kinase C activity to reduce evoked dopamine efflux from pheochromocytoma (PC12) cells. Endocrinology 144:94-100
Trachte, G J (2000) Depletion of natriuretic peptide C receptors eliminates inhibitory effects of C-type natriuretic peptide on evoked neurotransmitter efflux. J Pharmacol Exp Ther 294:210-5
Kanwal, S; Lowe, D G; Trachte, G J (1999) Intracellular fragments of the natriuretic peptide receptor-C (NPR-C) attenuate dopamine efflux. Endocrinology 140:1118-24
Kanwal, S; Elmquist, B J; Trachte, G J (1997) Atrial natriuretic peptide inhibits evoked catecholamine release by altering sensitivity to calcium. J Pharmacol Exp Ther 283:426-33
Trachte, G J; Kanwal, S; Elmquist, B J et al. (1995) C-type natriuretic peptide neuromodulates via ""clearance"" receptors. Am J Physiol 268:C978-84
Trachte, G J; Drewett, J G (1994) C-type natriuretic peptide neuromodulates independently of guanylyl cyclase activation. Hypertension 23:38-43
Trachte, G J (1993) Atrial natriuretic factor alters neurotransmission independently of guanylate cyclase-coupled receptors in the rabbit vas deferens. J Pharmacol Exp Ther 264:1227-33
Anand-Srivastava, M B; Trachte, G J (1993) Atrial natriuretic factor receptors and signal transduction mechanisms. Pharmacol Rev 45:455-97
Drewett, J G; Ziegler, R J; Trachte, G J (1992) Neuromodulatory effects of atrial natriuretic peptides correlate with an inhibition of adenylate cyclase but not an activation of guanylate cyclase. J Pharmacol Exp Ther 260:689-96