Gαq/p63RhoGEF Interaction in RhoA/Rho Kinase Signaling: Investigation in Gitelman's Syndrome and Implications with Hypertension

Overview

Journal J Endocrinol Invest

Publisher Springer

Specialty Endocrinology

Date 2017 Aug 26

PMID 28840514

Citations 2

Authors

E Pagnin

V Ravarotto

G Maiolino

E Naso

P A Davis

L A Calo

Affiliations

Soon will be listed here.

Abstract

Purpose: Gitelman's syndrome (GS) presents normo-hypotension and absence of cardiovascular-renal remodeling despite high angiotensin II (Ang II), activation of renin-angiotensin-aldosterone system and is a human model of endogenous antagonism of Ang II signaling, opposite to hypertension. GS's clinical presentation leads to questions regarding what features might be responsible. One area of investigation involves Ang II signaling. In hypertensive patients, RhoA/Rho kinase (RhoA/ROCK) pathway activation by Ang II is involved in hypertension development/maintenance and induction of long-term consequences (cardiovascular-renal remodeling), while GS has reduced p63RhoGEF gene and protein levels and ROCK activity. Ang II signaling is mediated by Gαq, which interacts with p63RhoGEF via the α6-αN linker connecting p63RhoGEF's DH and PH domains acting as a conformational switch to activate RhoA/ROCK signaling.

Methods: We have investigated in GS patients, the presence of mutations in either p63RhoGEF's α6-αN linker domain and in Gαq's Ala253, Trp263, and Tyr356 residues, crucial for p63RhoGEF-Gαq interplay.

Results: No mutations have been found in specific aminoacids of p63RhoGEF α6-αN linker and Gαq, key for p63RhoGEF/Gαq interplay.

Conclusions: Gitelman's syndrome normo/hypotension and lack of cardiovascular-renal remodeling are not due to mutations of p63RhoGEF α6-αN linker and Gαq interactions. This opens the way for investigations on different coding and no-coding regions (p63RhoGEF and Gαq promoters) and on altered transcriptional/post-transcriptional regulation. Clarification of how these biochemical/molecular mechanisms work/interact would provide insights into mechanisms involved in the GS's Ang II signaling fine tuning, in human physiology/pathophysiology in general and could also identify significant targets for intervention in the treatments of hypertension.

Citing Articles

ROCK (RhoA/Rho Kinase) in Cardiovascular-Renal Pathophysiology: A Review of New Advancements.

Seccia T, Rigato M, Ravarotto V, Calo L J Clin Med. 2020; 9(5).

PMID: 32370294 PMC: 7290501. DOI: 10.3390/jcm9051328.

Characteristics and Follow-Up of 13 pedigrees with Gitelman syndrome.

Zhong F, Ying H, Jia W, Zhou X, Zhang H, Guan Q J Endocrinol Invest. 2018; 42(6):653-665.

PMID: 30413979 PMC: 6531408. DOI: 10.1007/s40618-018-0966-1.

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