Functional Dosage of Muscarinic Cholinergic Receptor 3 Signalling, Not the Gene Dose, Determines Its Hypertension Pathogenesis
| Autor: | Julie-Émilie Huot-Marchard, Alan Y. Deng, Annie Ménard, Cristina Chauvet, Denis deBlois, Eric Thorin |
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| Rok vydání: | 2018 |
| Předmět: |
Epinephrine
Quantitative Trait Loci Congenic Mutation Missense Context (language use) 030204 cardiovascular system & hematology medicine.disease_cause Article Pathogenesis 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine Animals Congenic Adrenal Glands medicine Missense mutation Animals 030212 general & internal medicine Gene Knock-In Techniques Receptor Receptor Muscarinic M3 Mutation Rats Inbred Dahl business.industry Gene targeting Cell biology Disease Models Animal Hypertension Cardiology and Cardiovascular Medicine business Signal Transduction |
| Zdroj: | The Canadian journal of cardiology. 35(5) |
| ISSN: | 1916-7075 |
| Popis: | Background Multiple quantitative trait loci for blood pressure (BP) have been localized throughout human and rodent genomes. Few of them have been functionally identified especially in humans, and little is known about their pathogenic directionality when identified. We focused on Chrm3 encoding the muscarinic cholinergic receptor 3 (M3R) as the causal gene for C17QTL1 in the Dahl salt-sensitive rat model. Methods and Results Congenic knock-ins, gene-specific knockout, and ex vivo and in vivo function studies were applied in the Dahl salt-sensitive rat model of polygenic hypertension. A Chrm3 missense T1667C mutation in the last intracellular domain functionally correlated with a rise in BP increased the M3R signalling and resensitization, and adrenal epinephrogenesis. Gene targeting that abolished the M3R function without affecting any of noncoding Chrm3 variants caused a decrease in BP, indicating that the M3R-mediated signalling promotes hypertension. In contrast, removing 8 amino acids from the M3R first extracellular loop had no effect on BP. Conclusions The M3R-specialized signalling constitutes a new pathway of hypertension pathogenesis within the context of a polygenic and quantitative trait. Increased epinephrine in the circulation and secreted from the adrenal glands are suggestive of a molecular mechanism partially mediating M3R to promote hypertension. The structure-function relationships for various M3R domains in their effects on BP pave the way for identifying missense mutations that impact functions on BP as potential diagnostic targets. |
| Databáze: | OpenAIRE |
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