Document Detail

A PLCγ1-Dependent, Force-Sensitive Signaling Network in the Myogenic Constriction of Cerebral Arteries.
MedLine Citation:
PMID:  24866019     Owner:  NLM     Status:  In-Data-Review    
Maintaining constant blood flow in the face of fluctuations in blood pressure is a critical autoregulatory feature of cerebral arteries. An increase in pressure within the artery lumen causes the vessel to constrict through depolarization and contraction of the encircling smooth muscle cells. This pressure-sensing mechanism involves activation of two types of transient receptor potential (TRP) channels: TRPC6 and TRPM4. We provide evidence that the activation of the γ1 isoform of phospholipase C (PLCγ1) is critical for pressure sensing in cerebral arteries. Inositol 1,4,5-trisphosphate (IP3), generated by PLCγ1 in response to pressure, sensitized IP3 receptors (IP3Rs) to Ca(2+) influx mediated by the mechanosensitive TRPC6 channel, synergistically increasing IP3R-mediated Ca(2+) release to activate TRPM4 currents, leading to smooth muscle depolarization and constriction of isolated cerebral arteries. Proximity ligation assays demonstrated colocalization of PLCγ1 and TRPC6 with TRPM4, suggesting the presence of a force-sensitive, local signaling network comprising PLCγ1, TRPC6, TRPM4, and IP3Rs. Src tyrosine kinase activity was necessary for stretch-induced TRPM4 activation and myogenic constriction, consistent with the ability of Src to activate PLCγ isoforms. We conclude that contraction of cerebral artery smooth muscle cells requires the integration of pressure-sensing signaling pathways and their convergence on IP3Rs, which mediate localized Ca(2+)-dependent depolarization through the activation of TRPM4.
Albert L Gonzales; Ying Yang; Michelle N Sullivan; Lindsey Sanders; Fabrice Dabertrand; David C Hill-Eubanks; Mark T Nelson; Scott Earley
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Publication Detail:
Type:  Journal Article     Date:  2014-05-27
Journal Detail:
Title:  Science signaling     Volume:  7     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2014  
Date Detail:
Created Date:  2014-05-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  ra49     Citation Subset:  IM    
Copyright Information:
Copyright © 2014, American Association for the Advancement of Science.
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