Abstract
ABSTRACTWe have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit mesenteric arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in mesenteric arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone.
Highlights
Stimulation of plasmalemmal calcium-sensing receptors (CaSR) by an increase in extracellular Ca2+ concentration ([Ca2+]o) is involved in maintaining plasma Ca2+ homeostasis through regulation of parathyroid hormone synthesis and secretion from the parathyroid gland, intestinal Ca2+ absorption, and renal Ca2+ excretion [1,2,3]
GSK activated cation channel activity with a 6pS conductance in WT endothelial cells (ECs) but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production in ECs, which are responsible for endothelium-dependent vasorelaxations
In a recent pharmacological study investigating how stimulation of CaSR may induce these mechanisms, we reported that CaSR-mediated activation of endothelial heteromeric TRPV4/TRPC1 channels is required for NO production whereas a different cation channel in ECs is likely to be involved in IKCa channel activation [20]
Summary
Stimulation of plasmalemmal calcium-sensing receptors (CaSR) by an increase in extracellular Ca2+ concentration ([Ca2+]o) is involved in maintaining plasma Ca2+ homeostasis through regulation of parathyroid hormone synthesis and secretion from the parathyroid gland, intestinal Ca2+ absorption, and renal Ca2+ excretion [1,2,3]. It is apparent that CaSR are expressed in tissues not associated with plasma Ca2+ homeostasis, which suggests that CaSR are likely to be involved in regulating many different physiological systems. CaSR in the vasculature, with studies suggesting that stimulation of CaSR induces both vasoconstriction and vasorelaxation through diverse cellular mechanisms [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. In the presence of closely regulated plasma Ca2+ levels, stimulation of CaSR in the vasculature is considered possible as local [Ca2+]o is likely to rise sufficiently at the surface of cells due to active Ca2+ transport mechanisms such as the Ca2+-ATPase and the Na+-Ca2+ exchanger [3,11,21].
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