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Role of phosphorylation of the serine 552 residue in the regulation of NHE3 activity and subcellular distribution under physiological and pathophysiological conditions

Grant number: 13/04178-9
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2013
Effective date (End): September 30, 2017
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Renato de Oliveira Crajoinas
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated scholarship(s):16/24174-6 - Role of myosin IIA in angiotensin II-mediated regulation of NHE3 in the proximal tubule, BE.EP.DR


Na+/H+ exchanger isoform 3 (NHE3) is a transport protein responsible for reabsorption of the majority of the filtered NaCl, NaHCO3 and, consequently, water, in renal proximal tubules. This transporter therefore plays an essential role in regulating volume homeostasis and blood pressure levels. NHE3 activity is modified through a number of molecular mechanisms, including phosphorylation of th C-terminal residue serine 552, consensus site for protein kinase A (PKA). Studies have showed that there is a temporal dissociation between phosphorylation of serine 552 and PKA-mediated NHE3, suggesting that inhibition of NHE3 activity promoted by phosphorylation of this residue is not an immediate event. It is known that NHE3 is differentially regulated before and after the development of hypertension by mechanisms involving changes on the phosphorylation levels of serine 552 and redistribution of the transporter between the apical membrane microdomains of proximal tubules. In light of the above, this project aims to test the hypothesis that NHE3 activity is decreased when it is phosphorylated on serine 552 due to its redistribution between the apical membrane microdomains of renal proximal tubule and/or by interaction with different multimeric protein complexes. Subsequently, in an attempt to understand how phosphorylation of renal proximal tubule proteins may contribute to the development of hypertension, we intend to idenrify proteins that are differentially regulated by PKA before and after development of hypertension in the SHR. Finally, we intend to identify proteins that specifically associate with NHE3 when it is phosphorylated at serine 552 and to test the hypothesis that these proteins are unequally distributed between the apical membrane microdomains of renal proximal tubules before and after development of hypertension. (AU)