title: TRPM4 channels couple purinergic receptor mechanoactivation and myogenic tone development in cerebral parenchymal arterioles.
abstract: Cerebral parenchymal arterioles (PAs) have a critical role in assuring appropriate blood flow and perfusion pressure within the brain. They are unique in contrast to upstream pial arteries, as defined by their critical roles in neurovascular coupling, distinct sensitivities to chemical stimulants, and enhanced myogenic tone development. The objective of the present study was to reveal some of the unique mechanisms of myogenic tone regulation in the cerebral microcirculation. Here, we report that in vivo suppression of TRPM4 (transient receptor potential) channel expression, or inhibition of TRPM4 channels with 9-phenanthrol substantially reduced myogenic tone of isolated PAs, supporting a key role of TRPM4 channels in PA myogenic tone development. Further, downregulation of TRPM4 channels inhibited vasoconstriction induced by the specific P2Y4 and P2Y6 receptor ligands (UTPγS and UDP) by 37% and 42%, respectively. In addition, 9-phenanthrol substantially attenuated purinergic ligand-induced membrane depolarization and constriction of PAs, and inhibited ligand-evoked TRPM4 channel activation in isolated PA myocytes. In concert with our previous work showing the essential contributions of P2Y4 and P2Y6 receptors to myogenic regulation of PAs, the current results point to TRPM4 channels as an important link between mechanosensitive P2Y receptor activation and myogenic constriction of cerebral PAs.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Baylie
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tavares
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Brayden
mesh_terms: D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000502:physiology*; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D015536:Down-Regulation; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018408:Patch-Clamp Techniques; D010616:Phenanthrenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D010616:Phenanthrenes; D058470:Receptors, Purinergic P2Y; D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat; C091375:9-phenanthrol
references.citation: Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2234-8
references.pmid: 12388230
references.citation: Pharmacol Rev. 2013 Dec 11;66(1):102-92
references.pmid: 24335194
references.citation: Cardiovasc Res. 2010 Jan 1;85(1):204-13
references.pmid: 19640930
references.citation: J Cereb Blood Flow Metab. 2013 Feb;33(2):293-9
references.pmid: 23168530
references.citation: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2055-61
references.pmid: 15604128
references.citation: Int J Biochem Cell Biol. 2012 Sep;44(9):1505-10
references.pmid: 22677491
references.citation: Circ Res. 1984 Aug;55(2):197-202
references.pmid: 6744529
references.citation: Eur J Pharmacol. 2012 Dec 15;697(1-3):88-96
references.pmid: 23051677
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H2613-22
references.pmid: 17293488
references.citation: EMBO J. 2008 Dec 3;27(23):3092-103
references.pmid: 18987636
references.citation: J Physiol. 2013 Oct 15;591(20):5031-46
references.pmid: 23858011
references.citation: J Appl Physiol (1985). 2005 May;98(5):1940-8
references.pmid: 15626753
references.citation: Circ Res. 1990 Jan;66(1):8-17
references.pmid: 2403863
references.citation: Circ Res. 2002 Feb 22;90(3):248-50
references.pmid: 11861411
references.citation: Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H803-12
references.pmid: 21148767
references.citation: Am J Physiol Heart Circ Physiol. 2012 Mar 15;302(6):H1241-9
references.pmid: 22227128
references.citation: Br J Pharmacol. 2008 Apr;153(8):1697-705
references.pmid: 18297105
references.citation: Circ Res. 2012 Sep 28;111(8):1027-36
references.pmid: 22872152
references.citation: J Physiol. 2000 Sep 1;527 Pt 2:315-24
references.pmid: 10970432
references.citation: Am J Physiol Cell Physiol. 2010 Aug;299(2):C279-88
references.pmid: 20427713
references.citation: Nat Neurosci. 2006 Nov;9(11):1397-1403
references.pmid: 17013381
references.citation: Am J Physiol. 1998 May;274(5):L842-53
references.pmid: 9612301
references.citation: Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1616-30
references.pmid: 21357503
references.citation: Can J Physiol Pharmacol. 2012 Feb;90(2):175-86
references.pmid: 22308955
references.citation: Lancet Neurol. 2010 Jul;9(7):689-701
references.pmid: 20610345
references.citation: Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2196-201
references.pmid: 12388226
references.citation: J Physiol. 1998 Apr 1;508 ( Pt 1):199-209
references.pmid: 9490839
references.citation: Purinergic Signal. 2009 Sep;5(3):343-9
references.pmid: 19387869
references.citation: J Gen Physiol. 2006 Jun;127(6):611-22
references.pmid: 16702354
references.citation: J Cardiovasc Pharmacol. 2004 Jul;44(1):1-8
references.pmid: 15175551
references.citation: Circ Res. 2012 Jan 20;110(2):285-94
references.pmid: 22095728
references.citation: Circ Res. 2004 Oct 29;95(9):922-9
references.pmid: 15472118
references.citation: Am J Physiol Cell Physiol. 2010 Nov;299(5):C1195-202
references.pmid: 20826763
references.citation: Exp Physiol. 2012 Apr;97(4):544-55
references.pmid: 22090066
references.citation: Stroke. 2007 Aug;38(8):2322-8
references.pmid: 17585083
references.citation: Am J Physiol Heart Circ Physiol. 2000 Jun;278(6):H1751-61
references.pmid: 10843869
references.citation: Am J Physiol Heart Circ Physiol. 2001 Oct;281(4):H1759-66
references.pmid: 11557568
references.citation: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1088-100
references.pmid: 14592941