Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced nitric oxide production and vasorelaxation in rabbit mesenteric arteries

Autor: Harry Z.E. Greenberg, Kazi S. Jahan, Anthony P. Albert, Alexander Zargaran, W-S Vanessa Ho, Dhanak M Khan, Simonette R E Carlton-Carew
Rok vydání: 2017
Předmět:
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
Zdroj: Vascular Pharmacology
ISSN: 1537-1891
DOI: 10.1016/j.vph.2017.08.005
Popis: 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
Databáze: OpenAIRE
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