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Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/omega-hydroxylase/20-HETE pathways
- Source :
- Circulation research. 104(12)
- Publication Year :
- 2009
-
Abstract
- TRPC6 is a non–voltage-gated Ca 2+ entry/depolarization channel associated with vascular tone regulation and remodeling. Expressed TRPC6 channel responds to both neurohormonal and mechanical stimuli, the mechanism for which remains controversial. In this study, we examined the possible interactions of receptor and mechanical stimulations in activating this channel using the patch clamp technique. In HEK293 cells expressing TRPC6, application of mechanical stimuli (hypotonicity, shear, 2,4,6-trinitrophenol) caused, albeit not effective by themselves, a prominent potentiation of cationic currents ( I TRPC6 ) induced by a muscarinic receptor agonist carbachol. This effect was insensitive to a tarantula toxin GsMTx-4 (5 μmol/L). A similar extent of mechanical potentiation was observed after activation of I TRPC6 by GTPγS or a diacylglycerol analog 1-oleoyl-2-acetyl- sn -glycerol (OAG). Single TRPC6 channel activity evoked by carbachol was also enhanced by a negative pressure added in the patch pipette. Mechanical potentiation of carbachol- or OAG-induced I TRPC6 was abolished by small interfering RNA knockdown of cytosolic phospholipase A 2 or pharmacological inhibition of ω-hydroxylation of arachidonic acid into 20-HETE (20-hydroxyeicosatetraenoic acid). Conversely, direct application of 20-HETE enhanced both OAG-induced macroscopic and single channel TRPC6 currents. Essentially the same results were obtained for TRPC6-like cation channel in A7r5 myocytes, where its activation by noradrenaline or Arg8 vasopressin was greatly enhanced by mechanical stimuli via 20-HETE production. Furthermore, myogenic response of pressurized mesenteric artery was significantly enhanced by weak receptor stimulation dependently on 20-HETE production. These results collectively suggest that simultaneous operation of receptor and mechanical stimulations may synergistically amplify transmembrane Ca 2+ mobilization through TRPC6 activation, thereby enhancing the vascular tone via phospholipase C/diacylglycerol and phospholipase A 2 /ω-hydroxylase/20-HETE pathways.
- Subjects :
- Male
medicine.medical_specialty
Carbachol
Physiology
Spider Venoms
Cholinergic Agonists
Hydroxylation
Mechanotransduction, Cellular
TRPC6
Cell Line
Rats, Sprague-Dawley
chemistry.chemical_compound
Phospholipase A2
Internal medicine
Hydroxyeicosatetraenoic Acids
medicine
TRPC6 Cation Channel
Animals
Humans
Diacylglycerol kinase
TRPC Cation Channels
Phospholipase A
Muscle Cells
Phospholipase C
biology
Dose-Response Relationship, Drug
Receptors, Muscarinic
Rats
Phospholipases A2
Endocrinology
chemistry
Type C Phospholipases
biology.protein
Biophysics
Intercellular Signaling Peptides and Proteins
Arachidonic acid
Cytochrome P-450 CYP4A
Cardiology and Cardiovascular Medicine
Peptides
medicine.drug
Subjects
Details
- ISSN :
- 15244571
- Volume :
- 104
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Circulation research
- Accession number :
- edsair.doi.dedup.....af1f3e5db47675120e4cff1222f52d48