1. Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced nitric oxide production and vasorelaxation in rabbit mesenteric arteries
- Author
-
Harry Z.E. Greenberg, Kazi S. Jahan, Anthony P. Albert, Alexander Zargaran, W-S Vanessa Ho, Dhanak M Khan, and Simonette R E Carlton-Carew
- Subjects
Male ,0301 basic medicine ,TRPV4 ,medicine.medical_specialty ,Physiology ,Vasodilator Agents ,TRPV Cation Channels ,In Vitro Techniques ,Nitric Oxide ,Article ,Methoxamine ,Membrane Potentials ,CaSR, calcium-sensing receptors ,Nitric oxide ,TRPC1 ,03 medical and health sciences ,chemistry.chemical_compound ,Mesenteric Artery, Superior ,Internal medicine ,medicine ,Animals ,Calcium Signaling ,Mesenteric arteries ,TRPC Cation Channels ,Calcium signaling ,Pharmacology ,Membrane potential ,NO, nitric oxide ,TRPC1, canonical transient receptor potential channel 1 ,Dose-Response Relationship, Drug ,EC, endothelial cell ,Chemistry ,Endothelial Cells ,IKCa, intermediate conductance calcium-activated potassium channels ,3. Good health ,Vasodilation ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Biophysics ,TRPV4, transient receptor potential vanilloid-4 ,Molecular Medicine ,Rabbits ,Receptors, Calcium-Sensing ,Cation channel activity ,medicine.drug - Abstract
Stimulation of calcium-sensing receptors (CaSR) by increasing the external calcium concentration (Ca2 +]o) induces endothelium-dependent vasorelaxation through nitric oxide (NO) production and activation of intermediate Ca2 +-activated K+ currents (IKCa) channels in rabbit mesenteric arteries. The present study investigates the potential role of heteromeric TRPV4-TRPC1 channels in mediating these CaSR-induced vascular responses. Immunocytochemical and proximity ligation assays showed that TRPV4 and TRPC1 proteins were expressed and co-localised at the plasma membrane of freshly isolated endothelial cells (ECs). In wire myography studies, increasing [Ca2 +]o between 1 and 6 mM induced concentration-dependent relaxations of methoxamine (MO)-induced pre-contracted tone, which were inhibited by the TRPV4 antagonists RN1734 and HC067047, and the externally-acting TRPC1 blocking antibody T1E3. In addition, CaSR-evoked NO production in ECs measured using the fluorescent NO indicator DAF-FM was reduced by RN1734 and T1E3. In contrast, [Ca2 +]o-evoked perforated-patch IKCa currents in ECs were unaffected by RN1734 and T1E3. The TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent relaxation of MO-evoked pre-contracted tone and increased NO production, which were inhibited by the NO synthase inhibitor L-NAME, RN1734 and T1E3. GSK activated 6pS cation channel activity in cell-attached patches from ECs which was blocked by RN1734 and T1E3. These findings indicate that heteromeric TRPV4-TRPC1 channels mediate CaSR-induced vasorelaxation through NO production but not IKCa channel activation in rabbit mesenteric arteries. This further implicates CaSR-induced pathways and heteromeric TRPV4-TRPC1 channels in regulating vascular tone., Graphical abstract Image 1
- Published
- 2017
- Full Text
- View/download PDF