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GRK2 Up-Regulation Creates a Positive Feedback Loop for Catecholamine Production in Chromaffin Cells.

Authors: Jafferjee, Malika  Reyes Valero, Thairy  Marrero, Christine  McCrink, Katie A  Brill, Ava  Lymperopoulos, Anastasios 
Citation: Jafferjee M, etal., Mol Endocrinol. 2016 Mar;30(3):372-81. doi: 10.1210/me.2015-1305. Epub 2016 Feb 5.
Pubmed: (View Article at PubMed) PMID:26849467
DOI: Full-text: DOI:10.1210/me.2015-1305

Elevated sympathetic nervous system (SNS) activity aggravates several diseases, including heart failure. The molecular cause(s) underlying this SNS hyperactivity are not known. We have previously uncovered a neurohormonal mechanism, operating in adrenomedullary chromaffin cells, by which circulating catecholamine (CA) levels increase in heart failure: severe dysfunction of the adrenal a2-adrenergic receptors (ARs) due to the up-regulation of G protein-coupled receptor-kinase (GRK)-2, the kinase that desensitizes them. Herein we looked at the potential signaling mechanisms that bring about this GRK2 elevation in chromaffin cells. We found that chronic CA treatment of either PC12 or rat primary chromaffin cells can in itself result in GRK2 transcriptional up-regulation through a2ARs-Gi/o proteins-Src-ERK1/2. The resultant GRK2 increase severely enhances the a2AR desensitization/down-regulation elevating not only CA release but also CA biosynthesis, as evidenced by tyrosine hydroxylase up-regulation. Finally, GRK2 knockdown leads to enhanced apoptosis of PC12 cells, indicating an essential role for GRK2 in chromaffin cell homeostasis/survival. In conclusion, chromaffin cell GRK2 mediates a positive feedback loop that feeds into CA secretion, thereby enabling the adrenomedullary component of the SNS to turn itself on.

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CRRD Object Information
CRRD ID: 11572204
Created: 2016-12-21
Species: All species
Last Modified: 2016-12-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.