The overall objective of this research proposal is to decode the basic biochemical principles behind manifestation of salt sensitive and salt insensitive hypertension. Atrial natriuretic factor (ANF) and type B natriuretic peptide (BMP) are the key agents that control hypertension. ANF and BMP exhibit their physiological activity through ANF-receptor guanylate cyclase (ANF-RGC). ANF-RGC is a single transmembrane protein composed of modular blocks. The transmembrane module separates the protein into two regions, extracellular and intracellular. The extracellular region contains the ANF-binding domain. The intracellular region is composed of the following sequential modular blocks: the ATP-regulated module (ARM), the kinase homology domain (KHD), the dimerization and the catalytic domains. The ANF-RGC signal transduction mechanism is initiated by binding of ANF to the extracellular domain and culminates in the production of a second messenger cyclic GMP by the intracellular catalytic domain. The intermediate steps are unknown, however. The ARM is a critical transduction module, which stringently controls the ANF-dependent activity of the catalytic module. Its three-dimensional structure has been simulated. This structural model forms the working template for the proposed Specific Aims. The first three proposed aims are designed to elucidate the structure-based events by which ATP transduces the ANF signal into the production of cyclic GMP: 1) """"""""To elucidate the structural details of the ATP binding pocket of the ANF- RGC ARM domain"""""""";2) """"""""To determine the role of serine and threonine residues of the ARM domain in the process of ANF/ATP-dependent activation of ANF-RGC"""""""";3) """"""""To determine the amino acid residues of the ARM domain critical for the ANF/ATP-dependent activation of the catalytic domain"""""""". The fourth specific aim will provide an animal model for studying the basic mechanisms of hypertension and for ATP-related therapeutic treatments of hypertension: """"""""To evaluate the physiological contribution of the ATP signaling event through the creation and analysis of a transgenic mouse with the """"""""knock-in"""""""" mutation D646A"""""""".
These aims will be achieved through the use of a combination of molecular, biochemical, biophysical and immunologica! techniques together with computational modeling. The proposed studies are most fundamental in nature, yet they are directly applicable to the molecular understanding the disease processes resulting in hypertension, heart dystrophy, water balance and fluid secretion.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Thrasher, Terry N
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Salus University
Elkins Park
United States
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Duda, Teresa; Pertzev, Alexandre; Sharma, Rameshwar K (2013) The ANF-RGC gene motif (669)WTAPELL(675) is vital for blood pressure regulation: biochemical mechanism. Biochemistry 52:2337-47
Duda, Teresa; Pertzev, Alexandre; Sharma, Rameshwar K (2012) Ca(2+) modulation of ANF-RGC: new signaling paradigm interlocked with blood pressure regulation. Biochemistry 51:9394-405
Wen, Xiao-Hong; Duda, Teresa; Pertzev, Alexandre et al. (2012) S100B serves as a Ca(2+) sensor for ROS-GC1 guanylate cyclase in cones but not in rods of the murine retina. Cell Physiol Biochem 29:417-30
Duda, Teresa; Pertzev, Alexandre; Sharma, Rameshwar K (2012) Differential Ca(2+) sensor guanylate cyclase activating protein modes of photoreceptor rod outer segment membrane guanylate cyclase signaling. Biochemistry 51:4650-7
Duda, Teresa; Yadav, Prem; Sharma, Rameshwar K (2011) Allosteric modification, the primary ATP activation mechanism of atrial natriuretic factor receptor guanylate cyclase. Biochemistry 50:1213-25
Duda, Teresa; Pertzev, Alexandre; Sharma, Rameshwar K (2011) 657WTAPELL663 motif of the photoreceptor ROS-GC1: a general phototransduction switch. Biochem Biophys Res Commun 408:236-41
Duda, Teresa; Yadav, Prem; Sharma, Rameshwar K (2010) ATP allosteric activation of atrial natriuretic factor receptor guanylate cyclase. FEBS J 277:2550-3
Koch, Karl-W; Duda, Teresa; Sharma, Rameshwar K (2010) Ca(2+)-modulated vision-linked ROS-GC guanylate cyclase transduction machinery. Mol Cell Biochem 334:105-15
Jankowska, Anna; Burczy?ska, Beata; Duda, Teresa et al. (2010) Rod outer segment membrane guanylate cyclase type 1 (ROS-GC1) calcium-modulated transduction system in the sperm. Fertil Steril 93:904-12
Duda, Teresa; Sharma, Rameshwar K (2010) Distinct ONE-GC transduction modes and motifs of the odorants: Uroguanylin and CO(2). Biochem Biophys Res Commun 391:1379-84

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